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Kinoshita H, Walti CS, Webber K, Pezzella G, Jensen-Wachspress M, Lang H, Shuey K, Boonyaratanakornkit J, Pergam SA, Chu HY, Bollard CM, Keller MD, Hill JA. T Cell Immune Response to Influenza Vaccination When Administered Prior to and Following Autologous Chimeric Antigen Receptor-Modified T Cell Therapy. Transplant Cell Ther 2025; 31:327-338. [PMID: 40032074 PMCID: PMC12058394 DOI: 10.1016/j.jtct.2025.02.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/03/2025] [Accepted: 02/20/2025] [Indexed: 03/05/2025]
Abstract
Chimeric antigen receptor-modified T (CAR-T) cell therapies are gaining wider use in relapsed and refractory malignancies. However, data on vaccination in this population is lacking. We evaluated T cell responses in an established cohort of CAR-T recipients and healthy controls before and after 2019 to 2020 influenza vaccination. Peripheral blood mononuclear cells were isolated from healthy controls and patients who received the 2019 to 2020 influenza vaccine pre- or post-CD19, CD20, or B cell maturation antigen CAR-T. T cells were expanded in vitro for 10 days with peptide libraries for hemagglutinin (HA) and nucleoprotein from the 2019 to 2020 vaccine influenza A strains and analyzed by flow cytometry following interferon-γ/tumor necrosis factor-α (IFNγ/TNFα) intracellular staining. Antibody response was evaluated by a hemagglutination inhibition assay. Twenty-nine participants, including eight immunocompetent adults, seven pre-CAR-T, and 14 post-CAR-T patients, were evaluated. IFNγ+/TNFα+ T cell responses after influenza vaccination in healthy controls varied with an increased response to HA-Kansas after vaccination in 7/8 individuals. In the pre-CAR-T cohort, there was a rise in CD4+ T cell response to HA-Brisbane in 6/7 patients after vaccination that remained detectable in 3/4 evaluable patients 90 days post-CAR-T. Five of six patients who lacked an antibody response nonetheless demonstrated a T cell response to HA-Brisbane. There was no association between time since CAR-T administration, baseline immunoglobulin G, or absolute lymphocyte count and change in CD4+ T cell IFNγ+/TNFα+ response pre- to postvaccine for the post-CART cohort. These data demonstrate that cell-mediated immunity to the influenza vaccine can be elicited in patients vaccinated pre-CAR-T and sustained post-CAR-T, filling an important gap from lack of humoral responses.
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Affiliation(s)
- Hannah Kinoshita
- Center for Cancer and Immunology Research, Children's National Hospital, Washington, District of Columbia; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - Carla S Walti
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington; Infectious Disease and Hospital Epidemiology Division, University Hospital Basel, Basel, Switzerland
| | - Kathleen Webber
- Center for Cancer and Immunology Research, Children's National Hospital, Washington, District of Columbia
| | - Gloria Pezzella
- Center for Cancer and Immunology Research, Children's National Hospital, Washington, District of Columbia
| | - Mariah Jensen-Wachspress
- Center for Cancer and Immunology Research, Children's National Hospital, Washington, District of Columbia
| | - Haili Lang
- Center for Cancer and Immunology Research, Children's National Hospital, Washington, District of Columbia
| | - Kiel Shuey
- Department of Medicine, University of Washington, Seattle, Washington
| | - Jim Boonyaratanakornkit
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Steven A Pergam
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington; Clinical Research Division and Immunotherapy Integrated Research Center, Seattle, Washington
| | - Helen Y Chu
- Department of Medicine, University of Washington, Seattle, Washington
| | - Catherine M Bollard
- Center for Cancer and Immunology Research, Children's National Hospital, Washington, District of Columbia; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - Michael D Keller
- Center for Cancer and Immunology Research, Children's National Hospital, Washington, District of Columbia; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - Joshua A Hill
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington.
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Šťastná-Marková M, Hainz P, Kryštofová J, Macková J, Roubalová K, Vydra J, Němečková Š. Absence of pre-transplant T cell response against LAA is associated with Flt3-ITD mutation and increased relapse-risk in AML patients with HSCT. Immunotherapy 2025; 17:185-190. [PMID: 40099461 PMCID: PMC11951724 DOI: 10.1080/1750743x.2025.2478804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 03/10/2025] [Indexed: 03/19/2025] Open
Abstract
AIMS This study aimed to examine changes in the repertoire of functional T-cells specific for six leukemia-associated antigens (LAA), including WT1, PRAME, MUC1, CCNA1, NPM1, and NPM1c, during immune reconstitution following allogeneic transplantation of hematopoietic stem cells (HSCT) in patients with acute myeloid leukemia. PATIENTS & METHODS LAA-specific T cell response was measured by ELISPOT- IFNγ and intracellular cytokine staining in 47 patients before starting conditioning therapy (baseline) and 7 months after HSCT. RESULTS The positive cumulative LAA-specific T cell response before HSCT was associated with a decreased risk of relapse after HSCT. The prevalent genetic aberration - an internal tandem duplication of Fms 3 - related receptor tyrosine kinase, which has been previously implicated in immune escape mechanisms, is presented here for the first time as a factor associated with the absence of an adaptive T cell response against multiple LAAs. T-cell specific responses against wild-type and mutated NPM1 antigens were less frequent in the study cohort and did not correlate with mutations in the NPM1 gene. CONCLUSIONS Our results showed that the T-cell response to LAA can be reconstituted after HSCT. Measurement of functional pre-transplant T-cell responses against multiple LAAs could help to find patients with an increased risk of relapse.
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Affiliation(s)
- Markéta Šťastná-Marková
- Transplantation and Intensive Care Unit, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
- Institute of Clinical and Experimental Hematology of the 1st Faculty of Medicine of Charles University, Prague, Czech Republic
| | - Petr Hainz
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Jitka Kryštofová
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Jana Macková
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Kateřina Roubalová
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Jan Vydra
- Transplantation and Intensive Care Unit, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
- Institute of Clinical and Experimental Hematology of the 1st Faculty of Medicine of Charles University, Prague, Czech Republic
| | - Šárka Němečková
- Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
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Lara-de-León AG, Mora-Buch R, Cantó E, Peña-Gómez C, Rudilla F. Identification of Candidate Immunodominant Epitopes and Their HLA-Binding Prediction on BK Polyomavirus Proteins in Healthy Donors. HLA 2024; 104:e15722. [PMID: 39435889 DOI: 10.1111/tan.15722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 09/12/2024] [Accepted: 10/01/2024] [Indexed: 10/23/2024]
Abstract
BK polyomavirus infection is an important cause of graft loss in transplant patients, however, currently available therapies lack effectiveness against this pathogen. Identification of immunological targets for potential treatments is therefore necessary. The aim of this study was to predict candidates of immunodominant epitopes within four BK virus proteins (VP1, VP2, VP3 and LTA) using PBMCs from 44 healthy donors. We used the ELISpot epitope mapping method to evaluate the T-cell response, and HLA-peptide binding was predicted using the NetMHCpan algorithm. A total of 11 potential peptides were selected for VP1, 3 for VP2/VP3 and 13 for LTA. Greater reactivity was observed for VP1 and LTA proteins compared with VP2/VP3. Most of the peptides selected as potential immunodominant candidates were restricted towards several HLA class I and II alleles, with predominant HLA class I binding by computational predictions. Based on these findings, the sequences of the selected immunodominant epitopes candidates and their corresponding HLA restrictions could contribute to the optimisation of functional assays and aid in the design and improvement of immunotherapy strategies against BK virus infections.
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Affiliation(s)
- Ana Gabriela Lara-de-León
- Advanced & Cell Therapy Services, Banc de Sang i Teixits (Blood and Tissue Bank, BST), Barcelona, Spain
| | - Rut Mora-Buch
- Advanced & Cell Therapy Services, Banc de Sang i Teixits (Blood and Tissue Bank, BST), Barcelona, Spain
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
| | - Ester Cantó
- Advanced & Cell Therapy Services, Banc de Sang i Teixits (Blood and Tissue Bank, BST), Barcelona, Spain
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
| | - Cleofé Peña-Gómez
- Mental Health and Neurosciences, Mixt Unit, Parc Taulí Research and Innovation Institute (I3PT), Barcelona, Spain
| | - Francesc Rudilla
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
- Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits (Blood and Tissue Bank, BST), Barcelona, Spain
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Dadwal SS, Bansal R, Schuster MW, Yared JA, Myers GD, Matzko M, Adnan S, McNeel D, Ma J, Gilmore SA, Vasileiou S, Leen AM, Hill JA, Young JAH. Final outcomes from a phase 2 trial of posoleucel in allogeneic hematopoietic cell transplant recipients. Blood Adv 2024; 8:4740-4750. [PMID: 38593233 PMCID: PMC11413696 DOI: 10.1182/bloodadvances.2023011562] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 02/09/2024] [Accepted: 02/12/2024] [Indexed: 04/11/2024] Open
Abstract
ABSTRACT Allogeneic hematopoietic cell transplantation (allo-HCT) recipients are susceptible to viral infections. We conducted a phase 2 trial evaluating the safety and rate of clinically significant infections (CSIs; viremia requiring treatment or end-organ disease) after infusion of posoleucel, a partially HLA-matched, allogeneic, off-the-shelf, multivirus-specific T-cell investigational product for preventing CSIs with adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, or JC virus. This open-label trial enrolled allo-HCT recipients at high risk based on receiving grafts from umbilical cord blood, haploidentical, mismatched, or matched unrelated donors; post-HCT lymphocytes of <180/mm3; or use of T-cell depletion. Posoleucel dosing was initiated within 15 to 49 days of allo-HCT and subsequently every 14 days for up to 7 doses. The primary end point was the number of CSIs due to the 6 target viruses by week 14. Of the 26 patients enrolled, only 3 (12%) had a CSI by week 14, each with a single target virus. In vivo expansion of functional virus-specific T cells detected via interferon-γ enzyme-linked immunosorbent spot assay was associated with viral control. Persistence of posoleucel-derived T-cell clones for up to 14 weeks after the last infusion was confirmed by T-cell-receptor deep sequencing. Five patients (19%) had acute graft-versus-host disease grade 2 to 4. No patient experienced cytokine release syndrome. All 6 deaths were due to relapse or disease progression. allo-HCT recipients at high risk who received posoleucel had low rates of CSIs from 6 targeted viruses. Repeat posoleucel dosing was generally safe and well tolerated and associated with functional immune reconstitution. This trial was registered at www.ClinicalTrials.gov as #NCT04693637.
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Affiliation(s)
- Sanjeet S. Dadwal
- Division of Infectious Disease, City of Hope National Medical Center, Duarte, CA
| | - Rajat Bansal
- Department of Hematology, University of Kansas Medical Center, Kansas City, KS
| | - Michael W. Schuster
- Bone Marrow and Stem Cell Transplantation, Stony Brook University Hospital Cancer Center, Stony Brook, NY
| | - Jean A. Yared
- Department of Medicine, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
| | - Gary Douglas Myers
- Department of Pediatrics, Children's Mercy of Kansas City, Kansas City, MO
| | | | | | | | | | | | - Spyridoula Vasileiou
- AlloVir, Waltham, MA
- Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX
| | - Ann M. Leen
- AlloVir, Waltham, MA
- Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX
| | - Joshua A. Hill
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA
- University of Washington School of Medicine, Seattle, WA
| | - Jo-Anne H. Young
- Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, MN
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Schweitzer L, Muranski P. Virus-specific T cell therapy to treat refractory viral infections in solid organ transplant recipients. Am J Transplant 2024; 24:1558-1566. [PMID: 38857784 DOI: 10.1016/j.ajt.2024.05.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 05/29/2024] [Accepted: 05/31/2024] [Indexed: 06/12/2024]
Abstract
Solid organ transplant recipients require ongoing immunosuppression to prevent acute rejection, which puts them at risk of opportunistic infections. Viral infections are particularly challenging to prevent and treat as many establish latency and thus cannot be eliminated, whereas targets for small molecule antiviral medications are limited. Resistance to antivirals and unacceptable toxicity also complicate treatment. Virus-specific T cell therapies aim to restore host-specific immunity to opportunistic viruses that is lacking due to ongoing immunosuppressive therapy. This minireview will provide a state-of-the-art update of the current virus-specific T cell pipeline and translational research that is likely to lead to further treatment options for viral infections in solid organ transplant recipients.
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Affiliation(s)
- Lorne Schweitzer
- Department of Medicine, Division of Infectious Diseases, Columbia University Irving Medical Center, New York, New York, USA; Columbia Center for Translational Immunology, New York, New York, USA
| | - Pawel Muranski
- Department of Medicine, Division of Hematology, Columbia University Irving Medical Center, New York, New York, USA; Columbia Center for Translational Immunology, New York, New York, USA.
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Palianina D, Mietz J, Stühler C, Arnold B, Bantug G, Münz C, Chijioke O, Khanna N. Stem cell memory EBV-specific T cells control EBV tumor growth and persist in vivo. SCIENCE ADVANCES 2024; 10:eado2048. [PMID: 39178248 PMCID: PMC11343021 DOI: 10.1126/sciadv.ado2048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 07/19/2024] [Indexed: 08/25/2024]
Abstract
Adoptive T cell therapy (ACT), the therapeutic transfer of defined T cell immunity to patients, offers great potential in the fight against different human diseases including difficult-to-treat viral infections, but persistence and longevity of the cells are areas of concern. Very-early-differentiated stem cell memory T cells (TSCMs) have superior self-renewal, engraftment, persistence, and anticancer efficacy, but their potential for antiviral ACT remains unknown. Here, we developed a clinically scalable protocol for expanding Epstein-Barr virus (EBV)-specific TSCM-enriched T cells with high proportions of CD4+ T cells and broad EBV antigen coverage. These cells showed tumor control in a xenograft model of EBV-induced lymphoma and were superior to previous ACT protocols in terms of tumor infiltration, in vivo proliferation, persistence, proportion of functional CD4+ T cells, and diversity of EBV antigen specificity. Thus, our protocol may pave the way for the next generation of potent unmodified antigen-specific cell therapies for EBV-associated diseases, including tumors, and other indications.
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Affiliation(s)
- Darya Palianina
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Juliane Mietz
- Cellular Immunotherapy, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| | - Claudia Stühler
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Brice Arnold
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Glenn Bantug
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| | - Obinna Chijioke
- Cellular Immunotherapy, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
- Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland
| | - Nina Khanna
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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Vasileiou S, Kuvalekar M, Velazquez Y, Watanabe A, Leen AM, Gilmore SA. Phenotypic and functional characterization of posoleucel, a multivirus-specific T cell therapy for the treatment and prevention of viral infections in immunocompromised patients. Cytotherapy 2024; 26:869-877. [PMID: 38597860 DOI: 10.1016/j.jcyt.2024.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 02/09/2024] [Accepted: 03/13/2024] [Indexed: 04/11/2024]
Abstract
BACKGROUND Deficits in T cell immunity translate into increased risk of severe viral infection in recipients of solid organ and hematopoietic cell transplants. Thus, therapeutic strategies that employ the adoptive transfer of virus-specific T cells are being clinically investigated to treat and prevent viral diseases in these highly immunocompromised patients. Posoleucel is an off-the-shelf multivirus-specific T cell investigational product for the treatment and prevention of infections due to adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 or JC virus. METHODS Herein we perform extensive characterization of the phenotype and functional profile of posoleucel to illustrate the cellular properties that may contribute to its in vivo activity. RESULTS AND CONCLUSIONS Our results demonstrate that posoleucel is enriched for central and effector memory CD4+ and CD8+ T cells with specificity for posoleucel target viruses and expressing a broad repertoire of T cell receptors. Antigen-driven upregulation of cell-surface molecules and production of cytokine and effector molecules indicative of proliferation, co-stimulation, and cytolytic potential demonstrate the specificity of posoleucel and its potential to mount a broad, polyfunctional, and effective Th1-polarized antiviral response upon viral exposure. We also show the low risk for off-target and nonspecific effects as evidenced by the enrichment of posoleucel in memory T cells, low frequency of naive T cells, and lack of demonstrated alloreactivity in vitro. The efficacy of posoleucel is being explored in four placebo-controlled clinical trials in transplant recipients to treat and prevent viral infections (NCT05179057, NCT05305040, NCT04390113, NCT04605484).
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Affiliation(s)
- Spyridoula Vasileiou
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX; AlloVir, Inc., Waltham, MA
| | - Manik Kuvalekar
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX; AlloVir, Inc., Waltham, MA
| | - Yovana Velazquez
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX; AlloVir, Inc., Waltham, MA
| | - Ayumi Watanabe
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Ann M Leen
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX; AlloVir, Inc., Waltham, MA
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Rischall A, Olson A. SOHO State of the Art Updates and Next Questions | CTLs for Infections Following Stem Cell Transplantation. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2024; 24:340-347. [PMID: 38267354 DOI: 10.1016/j.clml.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 01/04/2024] [Accepted: 01/05/2024] [Indexed: 01/26/2024]
Abstract
Allogeneic hematopoietic stem cell transplantation (AHSCT) is an important modality in the treatment of acute leukemia and other hematologic disorders. The post-transplant period is associated with prolonged periods of impaired immune function. Delayed T-cell immune reconstitution is correlated with increased risk of viral, bacterial, and fungal infections. This risk increases with high intensity inductions regimens often required for alternative donor sources. Current therapies for prophylaxis and treatment of these infections are limited by poor efficacy and significant toxicity. Adoptive cell therapy with cytotoxic T lymphocytes (CTL) has proven to be both efficacious and safe in the management of post-transplant viral infections. Recent advances have led to faster production of CTLs and broadened applications for their use. In particular, the generation of third party CTLs has helped ameliorate the problems related to donor availability and product generation time. In this review we aim to describe both the history of CTL use and current advances in the field.
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Affiliation(s)
- Ariel Rischall
- Department of Medical Oncology, The University of Texas Medical Branch, Galveston, TX
| | - Amanda Olson
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.
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O’Reilly RJ, Prockop S, Oved JH. Virus-specific T-cells from third party or transplant donors for treatment of EBV lymphoproliferative diseases arising post hematopoietic cell or solid organ transplantation. Front Immunol 2024; 14:1290059. [PMID: 38274824 PMCID: PMC10808771 DOI: 10.3389/fimmu.2023.1290059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 12/14/2023] [Indexed: 01/27/2024] Open
Abstract
EBV+ lymphomas constitute a significant cause of morbidity and mortality in recipients of allogeneic hematopoietic cell (HCT) and solid organ transplants (SOT). Phase I and II trials have shown that in HCT recipients, adoptive transfer of EBV-specific T-cells from the HCT donor can safely induce durable remissions of EBV+ lymphomas including 70->90% of patients who have failed to respond to treatment with Rituximab. More recently, EBV-specific T-cells generated from allogeneic 3rd party donors have also been shown to induce durable remission of EBV+ lymphomas in Rituximab refractory HCT and SOT recipients. In this review, we compare results of phase I and II trials of 3rd party and donor derived EBV-specific T-cells. We focus on the attributes and limitations of each product in terms of access, safety, responses achieved and durability. The limited data available regarding donor and host factors contributing to T cell persistence is also described. We examine factors contributing to treatment failures and approaches to prevent or salvage relapse. Lastly, we summarize strategies to further improve results for virus-specific immunotherapies for post-transplant EBV lymphomas.
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Affiliation(s)
- Richard J. O’Reilly
- Department of Pediatrics, Stem Cell Transplantation and Cellular Therapies Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Susan Prockop
- Pediatric Stem Cell Transplantation, Boston Children’s Hospital/Dana-Farber Cancer Institute, Boston, MA, United States
| | - Joseph H. Oved
- Department of Pediatrics, Stem Cell Transplantation and Cellular Therapies Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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10
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Schreiber B, Tripathi S, Nikiforow S, Chandraker A. Adoptive Immune Effector Cell Therapies in Cancer and Solid Organ Transplantation: A Review. Semin Nephrol 2024; 44:151498. [PMID: 38555223 DOI: 10.1016/j.semnephrol.2024.151498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
Cancer is one of the most devastating complications of kidney transplantation and constitutes one of the leading causes of morbidity and mortality among solid organ transplantation (SOT) recipients. Immunosuppression, although effective in preventing allograft rejection, inherently inhibits immune surveillance against oncogenic viral infections and malignancy. Adoptive cell therapy, particularly immune effector cell therapy, has long been a modality of interest in both cancer and transplantation, though has only recently stepped into the spotlight with the development of virus-specific T-cell therapy and chimeric antigen receptor T-cell therapy. Although these modalities are best described in hematopoietic cell transplantation and hematologic malignancies, their potential application in the SOT setting may hold tremendous promise for those with limited therapeutic options. In this review, we provide a brief overview of the development of adoptive cell therapies with a focus on virus-specific T-cell therapy and chimeric antigen receptor T-cell therapy. We also describe the current experience of these therapies in the SOT setting as well as the challenges in their application and future directions in their development.
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Affiliation(s)
- Brittany Schreiber
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Sudipta Tripathi
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Sarah Nikiforow
- Division of Medical Oncology, Department of Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Anil Chandraker
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Division of Renal Medicine, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA.
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11
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Rocha FA, Silveira CRF, Dos Santos AF, Stefanini ACB, Hamerschlak N, Marti LC. Development of a highly cytotoxic, clinical-grade virus-specific T cell product for adoptive T cell therapy. Cell Immunol 2024; 395-396:104795. [PMID: 38101075 DOI: 10.1016/j.cellimm.2023.104795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 11/17/2023] [Accepted: 11/28/2023] [Indexed: 12/17/2023]
Abstract
At present, recipients of allogeneic hematopoietic stem-cells are still suffering from recurrent infections after transplantation. Infusion of virus-specific T cells (VST) post-transplant reportedly fights several viruses without increasing the risk of de novo graft-versus-host disease. This study targeted cytomegalovirus (CMV) for the development of an innovative approach for generating a very specific VST product following Good Manufacturing Practices (GMP) guidelines. We used a sterile disposable compartment named the Leukoreduction System Chamber (LRS-chamber) from the apheresis platelet donation kit as the starting material, which has demonstrated high levels of T cells. Using a combination of IL-2 and IL-7 we could improve expansion of CMV-specific T cells. Moreover, by developing and establishing a new product protocol, we were able to stimulate VST proliferation and favors T cell effector memory profile. The expanded VST were enriched in a closed automated system, creating a highly pure anti-CMV product, which was pre-clinically tested for specificity in vitro and for persistence, biodistribution, and toxicity in vivo using NOD scid mice. Our results demonstrated very specific VST, able to secrete high amounts of interferon only in the presence of cells infected by the human CMV strain (AD169), and innocuous to cells partially HLA compatible without viral infection.
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Affiliation(s)
- Fernanda Agostini Rocha
- Hospital Israelita Albert Einstein, Department of Experimental Research, Rua Comendador Elias Jafet, 755 Zip code: 05653 000, São Paulo, SP, Brazil
| | - Caio Raony Farina Silveira
- Hospital Israelita Albert Einstein, Department of Experimental Research, Rua Comendador Elias Jafet, 755 Zip code: 05653 000, São Paulo, SP, Brazil
| | - Ancély Ferreira Dos Santos
- Hospital Israelita Albert Einstein, Department of Experimental Research, Rua Comendador Elias Jafet, 755 Zip code: 05653 000, São Paulo, SP, Brazil
| | - Ana Carolina Buzzo Stefanini
- Hospital Israelita Albert Einstein, Department of Experimental Research, Rua Comendador Elias Jafet, 755 Zip code: 05653 000, São Paulo, SP, Brazil
| | - Nelson Hamerschlak
- Hospital Israelita Albert Einstein, Department of Bone Marrow Transplant, Avenida Albert Einstein, 627 Zip code: 05652 000, São Paulo, SP, Brazil
| | - Luciana Cavalheiro Marti
- Hospital Israelita Albert Einstein, Department of Experimental Research, Rua Comendador Elias Jafet, 755 Zip code: 05653 000, São Paulo, SP, Brazil.
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12
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Koukoulias K, Papayanni PG, Jones J, Kuvalekar M, Watanabe A, Velazquez Y, Gilmore S, Papadopoulou A, Leen AM, Vasileiou S. Assessment of the cytolytic potential of a multivirus-targeted T cell therapy using a vital dye-based, flow cytometric assay. Front Immunol 2023; 14:1299512. [PMID: 38187380 PMCID: PMC10766817 DOI: 10.3389/fimmu.2023.1299512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/05/2023] [Indexed: 01/09/2024] Open
Abstract
Reliable and sensitive characterization assays are important determinants of the successful clinical translation of immunotherapies. For the assessment of cytolytic potential, the chromium 51 (51Cr) release assay has long been considered the gold standard for testing effector cells. However, attaining the approvals to access and use radioactive isotopes is becoming increasingly complex, while technical aspects [i.e. sensitivity, short (4-6 hours) assay duration] may lead to suboptimal performance. This has been the case with our ex vivo expanded, polyclonal (CD4+ and CD8+) multivirus-specific T cell (multiVST) lines, which recognize 5 difficult-to-treat viruses [Adenovirus (AdV), BK virus (BKV), cytomegalovirus (CMV), Epstein Barr virus (EBV), and human herpes virus 6 (HHV6)] and when administered to allogeneic hematopoietic stem cell (HCT) or solid organ transplant (SOT) recipients have been associated with clinical benefit. However, despite mediating potent antiviral effects in vivo, capturing in vitro cytotoxic potential has proven difficult in a traditional 51Cr release assay. Now, in addition to cytotoxicity surrogates, including CD107a and Granzyme B, we report on an alternative, vital dye -based, flow cytometric platform in which superior sensitivity and prolonged effector:target co-culture duration enabled the reliable detection of both CD4- and CD8-mediated in vitro cytolytic activity against viral targets without non-specific effects.
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Affiliation(s)
- Kiriakos Koukoulias
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Penelope G. Papayanni
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Julia Jones
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Manik Kuvalekar
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Ayumi Watanabe
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Yovana Velazquez
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | | | - Anastasia Papadopoulou
- Hematology Department- Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, Thessaloniki, Greece
| | - Ann M. Leen
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Spyridoula Vasileiou
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
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13
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Gorriceta JH, Lopez Otbo A, Uehara G, Posadas Salas MA. BK viral infection: A review of management and treatment. World J Transplant 2023; 13:309-320. [PMID: 38174153 PMCID: PMC10758681 DOI: 10.5500/wjt.v13.i6.309] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/15/2023] [Accepted: 11/30/2023] [Indexed: 12/15/2023] Open
Abstract
BK viral infection remains to be a challenging post-transplant infection, which can result in kidney dysfunction. The mainstay approach to BK infection is reduction of immunosuppression. Alterations in immunosuppressive regimen with minimization of calcineurin inhibitors, use of mechanistic target of rapamycin inhibitors, and leflunomide have been attempted with variable outcomes. Over the past few years, investigators have explored potential therapeutic options for BK infection. Fluoroquinolone prophylaxis and treatment was found to have no benefit in kidney transplant recipients. The utility of cidofovir is limited by its nephrotoxicity. Intravenous immunoglobulin is becoming a popular option for treatment and prophylaxis for BK infection, as it increases the neutralizing antibody titers against the most common BK virus serotypes. Virus-specific T cell therapy is an emerging treatment option for BK viremia. In this review, we will explore management and therapeutic options for BK infection and recent evidence available in literature.
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Affiliation(s)
| | - Amy Lopez Otbo
- Department of Medicine, St. Luke’s Medical Center, Quezon 1112, Philippines
| | - Genta Uehara
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Maria Aurora Posadas Salas
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC 29425, United States
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14
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Gerbitz A, Gary R, Aigner M, Moosmann A, Kremer A, Schmid C, Hirschbuehl K, Wagner E, Hauptrock B, Teschner D, Roesler W, Spriewald B, Tischer J, Moi S, Balzer H, Schaffer S, Bausenwein J, Wagner A, Schmidt F, Brestrich J, Ullrich B, Maas S, Herold S, Strobel J, Zimmermann R, Weisbach V, Hansmann L, Lammoglia-Cobo F, Remberger M, Stelljes M, Ayuk F, Zeiser R, Mackensen A. Prevention of CMV/EBV reactivation by double-specific T cells in patients after allogeneic stem cell transplantation: results from the randomized phase I/IIa MULTIVIR-01 study. Front Immunol 2023; 14:1251593. [PMID: 37965339 PMCID: PMC10642256 DOI: 10.3389/fimmu.2023.1251593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 09/18/2023] [Indexed: 11/16/2023] Open
Abstract
Introduction Allogeneic stem cell transplantation is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population. Methods We report the results of a randomized controlled multi centre phase I/IIa study (MULTIVIR-01) using a newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. The study aimed at prevention and preemptive treatment of both viruses in patients after allogeneic stem cell transplantation targeting first infusion on day +30. Primary endpoints were acute transfusion reaction and acute-graft versus-host-disease after infusion of activated T cells. Results Thirty-three patients were screened and 9 patients were treated with a total of 25 doses of the T cell product. We show that central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation. Discussion Our study results indicate peptide stimulated epitope specific T cells derived from stem cell grafts can be administered safely for prevention and preemptive treatment of reactivation without evidence for induction of acute graft versus host disease. Clinical trial registration https://clinicaltrials.gov, identifier NCT02227641.
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Affiliation(s)
- Armin Gerbitz
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
- Princess Margaret Cancer Centre, Division of Medical Oncology/Hematology, Toronto, ON, Canada
| | - Regina Gary
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Michael Aigner
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Andreas Moosmann
- Department of Medicine 3, LMU University Hospital, Munich, Germany
- Helmholtz Center Munich, Institute of Virology, Munich, Germany
- Deutsches Zentrum für Infektionsforschung (DZIF) – German Center for Infection Research, Munich, Germany
| | - Anita Kremer
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Christoph Schmid
- Department of Medicine 2, University Hospital Augsburg, Augsburg, Germany
| | - Klaus Hirschbuehl
- Department of Medicine 2, University Hospital Augsburg, Augsburg, Germany
| | - Eva Wagner
- Department of Medicine 3, University Hospital Mainz, Mainz, Germany
| | - Beate Hauptrock
- Department of Medicine 3, University Hospital Mainz, Mainz, Germany
| | - Daniel Teschner
- Department of Medicine 3, University Hospital Mainz, Mainz, Germany
| | - Wolf Roesler
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Bernd Spriewald
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Johanna Tischer
- Department of Medicine 3, LMU University Hospital, Munich, Germany
| | - Stephanie Moi
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Heidi Balzer
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Stefanie Schaffer
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Judith Bausenwein
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Anja Wagner
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Franziska Schmidt
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
| | - Jens Brestrich
- Department of Hematology, Oncology and Tumor Immunology, Charite University Hospital Berlin, Berlin, Germany
| | - Barbara Ullrich
- Medical Center for Information and Communication Technology, University Hospital Erlangen, Erlangen, Germany
| | - Stefanie Maas
- Center for Clinical Studies (CCS), University Hospital Erlangen, Erlangen, Germany
| | - Susanne Herold
- Center for Clinical Studies (CCS), University Hospital Erlangen, Erlangen, Germany
| | - Julian Strobel
- Department of Transfusion Medicine, University Hospital Erlangen, Erlangen, Germany
| | - Robert Zimmermann
- Department of Transfusion Medicine, University Hospital Erlangen, Erlangen, Germany
| | - Volker Weisbach
- Department of Transfusion Medicine, University Hospital Erlangen, Erlangen, Germany
| | - Leo Hansmann
- Department of Hematology, Oncology and Tumor Immunology, Charite University Hospital Berlin, Berlin, Germany
| | - Fernanda Lammoglia-Cobo
- Department of Hematology, Oncology and Tumor Immunology, Charite University Hospital Berlin, Berlin, Germany
| | - Mats Remberger
- Department of Medical Sciences, Uppsala University and Clinical Research and Development Unit (KFUE), Uppsala University Hospital, Uppsala, Sweden
| | - Matthias Stelljes
- Department of Hematology/Oncology, University Hospital Muenster, Muenster, Germany
| | - Francis Ayuk
- Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany
| | - Robert Zeiser
- Department of Medicine 1, University Hospital Freiburg, Freiburg, Germany
| | - Andreas Mackensen
- Department of Medicine 5 Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany
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15
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Palianina D, Di Roberto RB, Castellanos-Rueda R, Schlatter F, Reddy ST, Khanna N. A method for polyclonal antigen-specific T cell-targeted genome editing (TarGET) for adoptive cell transfer applications. Mol Ther Methods Clin Dev 2023; 30:147-160. [PMID: 37448595 PMCID: PMC10336339 DOI: 10.1016/j.omtm.2023.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 06/15/2023] [Indexed: 07/15/2023]
Abstract
Adoptive cell therapy of donor-derived, antigen-specific T cells expressing native T cell receptors (TCRs) is a powerful strategy to fight viral infections in immunocompromised patients. Determining the fate of T cells following patient infusion hinges on the ability to track them in vivo. While this is possible by genetic labeling of parent cells, the applicability of this approach has been limited by the non-specificity of the edited T cells. Here, we devised a method for CRISPR-targeted genome integration of a barcoded gene into Epstein-Barr virus-antigen-stimulated T cells and demonstrated its use for exclusively identifying expanded virus-specific cell lineages. Our method facilitated the enrichment of antigen-specific T cells, which then mediated improved cytotoxicity against Epstein-Barr virus-transformed target cells. Single-cell and deep sequencing for lineage tracing revealed the expansion profile of specific T cell clones and their corresponding gene expression signature. This approach has the potential to enhance the traceability and the monitoring capabilities during immunotherapeutic T cell regimens.
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Affiliation(s)
- Darya Palianina
- Department of Biomedicine, University and University Hospital of Basel, 4056 Basel, Switzerland
| | - Raphaël B. Di Roberto
- Department of Biosystems Science and Engineering, ETH Zürich, 4058 Basel, Switzerland
| | - Rocío Castellanos-Rueda
- Department of Biosystems Science and Engineering, ETH Zürich, 4058 Basel, Switzerland
- Life Science Zurich Graduate School, Systems Biology, ETH Zürich, University of Zurich, 8057 Zürich, Switzerland
| | - Fabrice Schlatter
- Department of Biosystems Science and Engineering, ETH Zürich, 4058 Basel, Switzerland
| | - Sai T. Reddy
- Department of Biosystems Science and Engineering, ETH Zürich, 4058 Basel, Switzerland
| | - Nina Khanna
- Department of Biomedicine, University and University Hospital of Basel, 4056 Basel, Switzerland
- Divsion of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, 4031 Basel, Switzerland
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16
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Vasileiou S, Hill L, Kuvalekar M, Workineh AG, Watanabe A, Velazquez Y, Lulla S, Mooney K, Lapteva N, Grilley BJ, Heslop HE, Rooney CM, Brenner MK, Eagar TN, Carrum G, Grimes KA, Leen AM, Lulla P. Allogeneic, off-the-shelf, SARS-CoV-2-specific T cells (ALVR109) for the treatment of COVID-19 in high-risk patients. Haematologica 2023; 108:1840-1850. [PMID: 36373249 PMCID: PMC10316279 DOI: 10.3324/haematol.2022.281946] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 10/31/2022] [Indexed: 07/22/2023] Open
Abstract
Defects in T-cell immunity to SARS-CoV-2 have been linked to an increased risk of severe COVID-19 (even after vaccination), persistent viral shedding and the emergence of more virulent viral variants. To address this T-cell deficit, we sought to prepare and cryopreserve banks of virus-specific T cells, which would be available as a partially HLA-matched, off-the-shelf product for immediate therapeutic use. By interrogating the peripheral blood of healthy convalescent donors, we identified immunodominant and protective T-cell target antigens, and generated and characterized polyclonal virus-specific T-cell lines with activity against multiple clinically important SARS-CoV-2 variants (including 'delta' and 'omicron'). The feasibility of making and safely utilizing such virus-specific T cells clinically was assessed by administering partially HLA-matched, third-party, cryopreserved SARS-CoV-2-specific T cells (ALVR109) in combination with other antiviral agents to four individuals who were hospitalized with COVID-19. This study establishes the feasibility of preparing and delivering off-the-shelf, SARS-CoV-2-directed, virus-specific T cells to patients with COVID-19 and supports the clinical use of these products outside of the profoundly immune compromised setting (ClinicalTrials.gov number, NCT04401410).
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Affiliation(s)
- Spyridoula Vasileiou
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.
| | - LaQuisa Hill
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Manik Kuvalekar
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Aster G Workineh
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Ayumi Watanabe
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Yovana Velazquez
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Suhasini Lulla
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Kimberly Mooney
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Natalia Lapteva
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Bambi J Grilley
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Helen E Heslop
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Cliona M Rooney
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Malcolm K Brenner
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Todd N Eagar
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - George Carrum
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Kevin A Grimes
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Ann M Leen
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Premal Lulla
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
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17
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Capelli C, Cuofano C, Pavoni C, Frigerio S, Lisini D, Nava S, Quaroni M, Colombo V, Galli F, Bezukladova S, Panina-Bordignon P, Gaipa G, Comoli P, Cossu G, Martino G, Biondi A, Introna M, Golay J. Potency assays and biomarkers for cell-based advanced therapy medicinal products. Front Immunol 2023; 14:1186224. [PMID: 37359560 PMCID: PMC10288881 DOI: 10.3389/fimmu.2023.1186224] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/24/2023] [Indexed: 06/28/2023] Open
Abstract
Advanced Therapy Medicinal Products (ATMPs) based on somatic cells expanded in vitro, with or without genetic modification, is a rapidly growing area of drug development, even more so following the marketing approval of several such products. ATMPs are produced according to Good Manufacturing Practice (GMP) in authorized laboratories. Potency assays are a fundamental aspect of the quality control of the end cell products and ideally could become useful biomarkers of efficacy in vivo. Here we summarize the state of the art with regard to potency assays used for the assessment of the quality of the major ATMPs used clinic settings. We also review the data available on biomarkers that may substitute more complex functional potency tests and predict the efficacy in vivo of these cell-based drugs.
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Affiliation(s)
- Chiara Capelli
- Center of Cellular Therapy “G. Lanzani”, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Carolina Cuofano
- Center of Cellular Therapy “G. Lanzani”, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Chiara Pavoni
- Center of Cellular Therapy “G. Lanzani”, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Simona Frigerio
- Cell Therapy Production Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Daniela Lisini
- Cell Therapy Production Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Sara Nava
- Cell Therapy Production Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Michele Quaroni
- Laboratory of Cell and Gene Therapy Stefano Verri, ASST Monza Ospedale San Gerardo, Monza, Italy
| | - Valentina Colombo
- Laboratory of Cell and Gene Therapy Stefano Verri, ASST Monza Ospedale San Gerardo, Monza, Italy
| | - Francesco Galli
- Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health (FBMH), University of Manchester, Manchester, United Kingdom
| | - Svetlana Bezukladova
- Università Vita-Salute San Raffaele, Milan, Italy
- IRCCS San Raffaele Hospital, Neuroimmunology Unit, Division of Neuroscience, Milan, Italy
| | - Paola Panina-Bordignon
- Università Vita-Salute San Raffaele, Milan, Italy
- IRCCS San Raffaele Hospital, Neuroimmunology Unit, Division of Neuroscience, Milan, Italy
| | - Giuseppe Gaipa
- Laboratory of Cell and Gene Therapy Stefano Verri, ASST Monza Ospedale San Gerardo, Monza, Italy
| | - Patrizia Comoli
- Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Giulio Cossu
- Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health (FBMH), University of Manchester, Manchester, United Kingdom
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Gianvito Martino
- IRCCS San Raffaele Hospital, Neuroimmunology Unit, Division of Neuroscience, Milan, Italy
- Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Andrea Biondi
- Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Martino Introna
- Center of Cellular Therapy “G. Lanzani”, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Josée Golay
- Center of Cellular Therapy “G. Lanzani”, ASST Papa Giovanni XXIII, Bergamo, Italy
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18
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Tischer-Zimmermann S, Salzer E, Bitencourt T, Frank N, Hoffmann-Freimüller C, Stemberger J, Maecker-Kolhoff B, Blasczyk R, Witt V, Fritsch G, Paster W, Lion T, Eiz-Vesper B, Geyeregger R. Rapid and sustained T cell-based immunotherapy against invasive fungal disease via a combined two step procedure. Front Immunol 2023; 14:988947. [PMID: 37090716 PMCID: PMC10114046 DOI: 10.3389/fimmu.2023.988947] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 03/09/2023] [Indexed: 04/25/2023] Open
Abstract
Introduction Aspergillus fumigatus (Asp) infections constitute a major cause of morbidity and mortality in patients following allogeneic hematopoietic stem cell transplantation (HSCT). In the context of insufficient host immunity, antifungal drugs show only limited efficacy. Faster and increased T-cell reconstitution correlated with a favorable outcome and a cell-based therapy approach strongly indicated successful clearance of fungal infections. Nevertheless, complex and cost- or time-intensive protocols hampered their implementation into clinical application. Methods To facilitate the clinical-scale manufacturing process of Aspergillus fumigatus-specific T cells (ATCs) and to enable immediate (within 24 hours) and sustained (12 days later) treatment of patients with invasive aspergillosis (IA), we adapted and combined two complementary good manufacturing practice (GMP)-compliant approaches, i) the direct magnetic enrichment of Interferon-gamma (IFN-γ) secreting ATCs using the small-scale Cytokine Secretion Assay (CSA) and ii) a short-term in vitro T-cell culture expansion (STE), respectively. We further compared stimulation with two standardized and commercially available products: Asp-lysate and a pool of overlapping peptides derived from different Asp-proteins (PepMix). Results For the fast CSA-based approach we detected IFN-γ+ ATCs after Asp-lysate- as well as PepMix-stimulation but with a significantly higher enrichment efficiency for stimulation with the Asp-lysate when compared to the PepMix. In contrast, the STE approach resulted in comparably high ATC expansion rates by using Asp-lysate or PepMix. Independent of the stimulus, predominantly CD4+ helper T cells with a central-memory phenotype were expanded while CD8+ T cells mainly showed an effector-memory phenotype. ATCs were highly functional and cytotoxic as determined by secretion of granzyme-B and IFN-γ. Discussion For patients with IA, the immediate adoptive transfer of IFN-γ+ ATCs followed by the administration of short-term in vitro expanded ATCs from the same donor, might be a promising therapeutic option to improve the clinical outcome.
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Affiliation(s)
- Sabine Tischer-Zimmermann
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Elisabeth Salzer
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
- Department of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
- Department of Pediatrics, Laboratory for Pediatric Immunology, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
| | | | - Nelli Frank
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | | | - Julia Stemberger
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | - Britta Maecker-Kolhoff
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Volker Witt
- Department of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
- Department of Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Gerhard Fritsch
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | - Wolfgang Paster
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | - Thomas Lion
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | - Britta Eiz-Vesper
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - René Geyeregger
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
- Department of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
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19
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Linn YC, Sundar Raj K, Teo B, Phang CY, Chittezhath M, Koh M. A cost-effective strategy for selection of third-party donors for a virus-specific T-cell bank for an Asian patient population. Cytotherapy 2023; 25:510-520. [PMID: 36882347 DOI: 10.1016/j.jcyt.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 12/31/2022] [Accepted: 02/04/2023] [Indexed: 03/08/2023]
Abstract
BACKGROUND AIMS Third party virus-specific T cells (VST) has shown efficacy for opportunistic virus infection which do not have effective treatment or are drug-refractory. We describe our preparatory work in setting up a third-party VST bank for a multi-ethnic Asian population. METHODS Discarded white cells from regular blood bank plateletpheresis donors with known locally prevalent HLA antigens were cultured in small scale to generate VST against Adenovirus, BK virus, Cytomegalovirus, Epstein-Barr virus, and Human Herpes Virus 6. Multi-virus specific T cells (multi-VST) were also generated against all 5 viruses in single cultures. A strategy of allelic typing for donors with good and broad-spectrum cytotoxicity together with consideration on HLA restriction for the virus epitope was used to select combinations of VST lines for a hypothetical third party VST bank. The breadth of coverage based on these selection criteria was validated using our database of 100 post haematopoietic stem cell transplant patients. RESULTS We show that 50%, 42%, 56%, 56% and 42% of single VST cultures demonstrated specific cytotoxicity against AdV, BKV, CMV, EBV and HHV6 respectively. Twenty four of the 36 multi-VST lines showed activity against at least 2 of the 5 viruses studied. A carefully selected combination of just 6 VST lines can offer VST with at least 1 allelic match to 99% of potential recipients, while 92% can find 2 allelic matches and 79% can find 3 allelic matches. CONCLUSIONS This preparatory work confirms that a cost-effective strategy recruiting a small number of pre-characterized donors can generate VST lines with broad coverage for a multi-ethnic Asian patient population, thereby laying the foundation for setting up of a third party VST bank for Asian patients.
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Affiliation(s)
- Yeh-Ching Linn
- Department of Hematology, Singapore General Hospital, Singapore, Republic of Singapore.
| | | | - Bryan Teo
- Department of Clinical and Translational Research, Singapore General Hospital, Singapore, Republic of Singapore
| | - Chew-Yen Phang
- Patient Services, Blood Services Group, Health Sciences Authority, Singapore, Republic of Singapore
| | - Manesh Chittezhath
- Department of Hematology, Singapore General Hospital, Singapore, Republic of Singapore; Cell Therapy Facility, Blood Services Group, Health Sciences Authority, Singapore, Republic of Singapore
| | - Mickey Koh
- Cell Therapy Facility, Blood Services Group, Health Sciences Authority, Singapore, Republic of Singapore; Infection and Immunity Clinical Academic Group, St George's, University of London, London, UK
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20
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Mestiri S, Merhi M, Inchakalody VP, Taib N, Smatti MK, Ahmad F, Raza A, Ali FH, Hydrose S, Fernandes Q, Ansari AW, Sahir F, Al-Zaidan L, Jalis M, Ghoul M, Allahverdi N, Al Homsi MU, Uddin S, Jeremijenko AM, Nimir M, Abu-Raddad LJ, Abid FB, Zaqout A, Alfheid SR, Saqr HMH, Omrani AS, Hssain AA, Al Maslamani M, Yassine HM, Dermime S. Persistence of spike-specific immune responses in BNT162b2-vaccinated donors and generation of rapid ex-vivo T cells expansion protocol for adoptive immunotherapy: A pilot study. Front Immunol 2023; 14:1061255. [PMID: 36817441 PMCID: PMC9933868 DOI: 10.3389/fimmu.2023.1061255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/11/2023] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION The BNT162b2 mRNA-based vaccine has shown high efficacy in preventing COVID-19 infection but there are limited data on the types and persistence of the humoral and T cell responses to such a vaccine. METHODS Here, we dissect the vaccine-induced humoral and cellular responses in a cohort of six healthy recipients of two doses of this vaccine. RESULTS AND DISCUSSION Overall, there was heterogeneity in the spike-specific humoral and cellular responses among vaccinated individuals. Interestingly, we demonstrated that anti-spike antibody levels detected by a novel simple automated assay (Jess) were strongly correlated (r=0.863, P<0.0001) with neutralizing activity; thus, providing a potential surrogate for neutralizing cell-based assays. The spike-specific T cell response was measured with a newly modified T-spot assay in which the high-homology peptide-sequences cross-reactive with other coronaviruses were removed. This response was induced in 4/6 participants after the first dose, and all six participants after the second dose, and remained detectable in 4/6 participants five months post-vaccination. We have also shown for the first time, that BNT162b2 vaccine enhanced T cell responses also against known human common viruses. In addition, we demonstrated the efficacy of a rapid ex-vivo T cell expansion protocol for spike-specific T cell expansion to be potentially used for adoptive-cell therapy in severe COVID-19, immunocompromised individuals, and other high-risk groups. There was a 9 to 13.7-fold increase in the number of expanded T cells with a significant increase of anti-spike specific response showing higher frequencies of both activation and cytotoxic markers. Interestingly, effector memory T cells were dominant in all four participants' CD8+ expanded memory T cells; CD4+ T cells were dominated by effector memory in 2/4 participants and by central memory in the remaining two participants. Moreover, we found that high frequencies of CD4+ terminally differentiated memory T cells were associated with a greater reduction of spike-specific activated CD4+ T cells. Finally, we showed that participants who had a CD4+ central memory T cell dominance expressed a high CD69 activation marker in the CD4+ activated T cells.
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Affiliation(s)
- Sarra Mestiri
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Maysaloun Merhi
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Varghese P. Inchakalody
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Nassiba Taib
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Maria K. Smatti
- Qatar University Biomedical Research Center, Qatar University, Doha, Qatar
| | - Fareed Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Afsheen Raza
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Fatma H. Ali
- Qatar University Biomedical Research Center, Qatar University, Doha, Qatar
| | - Shereena Hydrose
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Queenie Fernandes
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- College of Medicine, Qatar University, Doha, Qatar
| | - Abdul W. Ansari
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Fairooz Sahir
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Lobna Al-Zaidan
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Munir Jalis
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Mokhtar Ghoul
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Niloofar Allahverdi
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Mohammed U. Al Homsi
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | | | - Mai Nimir
- Communicable Disease Center, Hamad Medical Corporation, Doha, Qatar
| | - Laith J. Abu-Raddad
- Infectious Disease Epidemiology Group, Weill Cornell Medicine–Qatar, Cornell University, Qatar Foundation–Education City, Doha, Qatar
- World Health Organization Collaborating Centre for Disease Epidemiology Analytics on HIV/AIDS, Sexually Transmitted Infections, and Viral Hepatitis, Weill Cornell Medicine–Qatar, Cornell University, Qatar Foundation–Education City, Doha, Qatar
- Department of Population Health Sciences, Weill Cornell Medicine, Cornell University, New York, NY, United States
| | - Fatma Ben Abid
- Communicable Disease Center, Hamad Medical Corporation, Doha, Qatar
| | - Ahmed Zaqout
- Communicable Disease Center, Hamad Medical Corporation, Doha, Qatar
| | | | | | - Ali S. Omrani
- College of Medicine, Qatar University, Doha, Qatar
- Communicable Disease Center, Hamad Medical Corporation, Doha, Qatar
| | - Ali Ait Hssain
- Medical Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
| | | | - Hadi M. Yassine
- Qatar University Biomedical Research Center, Qatar University, Doha, Qatar
| | - Said Dermime
- Translational Cancer Research Facility, National Center for Cancer Care and Research/ Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
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Pathogen-specific T Cells: Targeting Old Enemies and New Invaders in Transplantation and Beyond. Hemasphere 2023; 7:e809. [PMID: 36698615 PMCID: PMC9831191 DOI: 10.1097/hs9.0000000000000809] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 11/07/2022] [Indexed: 01/27/2023] Open
Abstract
Adoptive immunotherapy with virus-specific cytotoxic T cells (VSTs) has evolved over the last three decades as a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after solid organ or allogeneic hematopoietic cell-transplantation (allo-HCT). Since the early proof-of-principle studies demonstrating that seropositive donor-derived T cells, specific for the commonest pathogens post transplantation, namely cytomegalovirus or Epstein-Barr virus (EBV) and generated by time- and labor-intensive protocols, could effectively control viral infections, major breakthroughs have then streamlined the manufacturing process of pathogen-specific T cells (pSTs), broadened the breadth of target recognition to even include novel emerging pathogens and enabled off-the-shelf administration or pathogen-naive donor pST production. We herein review the journey of evolution of adoptive immunotherapy with nonengineered, natural pSTs against infections and virus-associated malignancies in the transplant setting and briefly touch upon recent achievements using pSTs outside this context.
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22
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Activated T cell therapy targeting glioblastoma cancer stem cells. Sci Rep 2023; 13:196. [PMID: 36604465 PMCID: PMC9814949 DOI: 10.1038/s41598-022-27184-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 12/27/2022] [Indexed: 01/06/2023] Open
Abstract
Naïve T cells become effector T cells following stimulation by antigen-loaded dendritic cells (DCs) and sequential cytokine activation. We aimed to develop procedures to efficiently activate T cells with tumor-associated antigens (TAAs) to glioblastoma (GBM) stem cells. To remove antigen presentation outside of the immunosuppressive tumor milieu, three different glioma stem cell (GSC) specific antigen sources to load DCs were compared in their ability to stimulate lymphocytes. An activated T cell (ATC) protocol including cytokine activation and expansion in culture to target GSCs was generated and optimized for a planned phase I clinical trial. We compared three different antigen-loading methods on DCs to effectively activate T cells, which were GBM patient-derived GSC-lysate, acid-eluate of GSCs and synthetic peptides derived from proteins expressed in GSCs. DCs derived from HLA-A2 positive blood sample were loaded with TAAs. Autologous T cells were activated by co-culturing with loaded DCs. Efficiency and cytotoxicity of ATCs were evaluated by targeting TAA-pulsed DCs or T2 cells, GSCs, or autologous PHA-blasts. Characteristics of ATCs were evaluated by Flow Cytometry and ELISpot assay, which showed increased number of ATCs secreting IFN-γ targeting GSCs as compared with non-activated T cells and unloaded target cells. Neither GSC-lysate nor acid-eluate loading showed enhancement in response of ATCs but the synthetic peptide pool showed significantly increased IFN-γ secretion and increased cytotoxicity towards target cells. These results demonstrate that ATCs activated using a TAA synthetic peptide pool efficiently enhance cytotoxicity specifically to target cells including GSC.
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23
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Arunachalam AK, Palani HK, Yasar M, Kulkarni U, Mathews V, George B. Generation of good manufacturing practice grade virus-specific T cells for the management of post-transplant CMV infections. J Immunol Methods 2022; 511:113375. [PMID: 36243107 DOI: 10.1016/j.jim.2022.113375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 10/08/2022] [Accepted: 10/08/2022] [Indexed: 11/06/2022]
Abstract
Adoptive transfer of antigen-specific T cells has recently emerged as a successful strategy to treat viral infections following hematopoietic cell transplantation (HCT). Ex-vivo expanded donor-derived virus-specific T cells (VSTs) can be safe and effective, devoid of all the drug-related adverse effects. The study aimed to manufacture cGMP grade VSTs from healthy donors, characterize the VST product and demonstrate its safety and efficacy. Peripheral blood mononuclear cells (PBMCs) collected from six healthy donors were stimulated with pepmix that mimics the pp65 antigenic epitope of CMV and cultured for 14 days in G-Rex culture tubes. Post pepmix exposure and expansion the median CD3% was 98.8% (range:95.5% to 99.9%) while the median CD4% and CD8% were 49.1% (range:21.3% to 86.6%) and 43.9% (range:12.7% to 75.5%) respectively. The percentage of IFNγ+ cells was much higher among the CD8+ T cells (median - 18.47%; range 6.50% - 45.82%) when compared to CD4+ T cells (median - 2.74%; range 0.47% - 18.58%) and there was a switch from the CD45RA+ naive phenotype to CD45RA- effector memory phenotype in the 4 samples that achieved a >5 fold expansion. The VSTs were cytotoxic to the pepmix pulsed lymphoblasts (efficacy) while they did not induce cytolysis in the lymphoblasts that were not exposed to the pepmix (safety). This feasibility exercise helped us optimize the starting cell dose for the culture and clinical grade culture strategies, subset characterization and cytotoxicity assays. The approach could be applied to the clinical practice where virus-specific T cell infusions could be given for post-transplant viral infections.
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Affiliation(s)
| | | | - Mohammed Yasar
- Department of Haematology, Christian Medical College, Vellore 632004, India
| | - Uday Kulkarni
- Department of Haematology, Christian Medical College, Vellore 632004, India
| | - Vikram Mathews
- Department of Haematology, Christian Medical College, Vellore 632004, India
| | - Biju George
- Department of Haematology, Christian Medical College, Vellore 632004, India
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24
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Antigen-Specific T Cells and SARS-CoV-2 Infection: Current Approaches and Future Possibilities. Int J Mol Sci 2022; 23:ijms232315122. [PMID: 36499448 PMCID: PMC9737069 DOI: 10.3390/ijms232315122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 11/25/2022] [Accepted: 11/26/2022] [Indexed: 12/05/2022] Open
Abstract
COVID-19, a significant global health threat, appears to be an immune-related disease. Failure of effective immune responses in initial stages of infection may contribute to development of cytokine storm and systemic inflammation with organ damage, leading to poor clinical outcomes. Disease severity and the emergence of new SARS-CoV-2 variants highlight the need for new preventative and therapeutic strategies to protect the immunocompromised population. Available data indicate that these people may benefit from adoptive transfer of allogeneic SARS-CoV-2-specific T cells isolated from convalescent individuals. This review first provides an insight into the mechanism of cytokine storm development, as it is directly related to the exhaustion of T cell population, essential for viral clearance and long-term antiviral immunity. Next, we describe virus-specific T lymphocytes as a promising and efficient approach for the treatment and prevention of severe COVID-19. Furthermore, other potential cell-based therapies, including natural killer cells, regulatory T cells and mesenchymal stem cells are mentioned. Additionally, we discuss fast and effective ways of producing clinical-grade antigen-specific T cells which can be cryopreserved and serve as an effective "off-the-shelf" approach for rapid treatment of SARS-CoV-2 infection in case of sudden patient deterioration.
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25
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Motta CM, Keller MD, Bollard CM. Applications of Virus specific T cell Therapies Post BMT. Semin Hematol 2022; 60:10-19. [PMID: 37080705 DOI: 10.1053/j.seminhematol.2022.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Hematopoietic stem cell transplantation (HSCT) has been used as a curative standard of care for moderate to severe primary immunodeficiency disorders as well as relapsed hematologic malignancies for over 50 years [1,2]. However, chronic and refractory viral infections remain a leading cause of morbidity and mortality in the immune deficient period following HSCT, where use of available antiviral pharmacotherapies is limited by toxicity and emerging resistance [3]. Adoptive immunotherapy using virus-specific T cells (VSTs) has been explored for over 2 decades [4,5] in patients post-HSCT and has been shown prior phase I-II studies to be safe and effective for treatment or preventions of viral infections including cytomegalovirus, Epstein-Barr virus, BK virus, and adenovirus with minimal toxicity and low risk of graft vs host disease [6-9]. This review summarizes methodologies to generate VSTs the clinical results utilizing VST therapeutics and the challenges and future directions for the field.
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26
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Abstract
Epstein-Barr virus (EBV) is a lymphotropic virus responsible for numerous epithelial and lymphoid cell malignancies, including gastric carcinoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and Burkitt lymphoma. Hundreds of thousands of people worldwide get infected with this virus, and in most cases, this viral infection leads to cancer. Although researchers are trying to develop potential vaccines and drug therapeutics, there is still no effective vaccine to combat this virus. In this study, the immunoinformatics approach was utilized to develop a potential multiepitope subunit vaccine against the two most common subtypes of EBV, targeting three of their virulent envelope glycoproteins. Eleven cytotoxic T lymphocyte (CTL) epitopes, 11 helper T lymphocyte (HTL) epitopes, and 10 B-cell lymphocyte (BCL) epitopes were predicted to be antigenic, nonallergenic, nontoxic, and fully conserved among the two subtypes, and nonhuman homologs were used for constructing the vaccine after much analysis. Later, further validation experiments, including molecular docking with different immune receptors (e.g., Toll-like receptors [TLRs]), molecular dynamics simulation analyses (including root means square deviation [RMSD], root mean square fluctuation [RMSF], radius of gyration [Rg], principal-component analysis [PCA], dynamic cross-correlation [DCC], definition of the secondary structure of proteins [DSSP], and Molecular Mechanics Poisson-Boltzmann Surface Area [MM-PBSA]), and immune simulation analyses generated promising results, ensuring the safe and stable response of the vaccine with specific immune receptors after potential administration within the human body. The vaccine's high binding affinity with TLRs was revealed in the docking study, and a very stable interaction throughout the simulation proved the potential high efficacy of the proposed vaccine. Further, in silico cloning was also conducted to design an efficient mass production strategy for future bulk industrial vaccine production. IMPORTANCE Epstein-Barr virus (EBV) vaccines have been developing for over 30 years, but polyphyletic and therapeutic vaccines have failed to get licensed. Our vaccine surpasses the limitations of many such vaccines and remains very promising, which is crucial because the infection rate is higher than most viral infections, affecting a whopping 90% of the adult population. One of the major identifications covers a holistic analysis of populations worldwide, giving us crucial information about its effectiveness for everyone's unique immunological system. We targeted three glycoproteins that enhance the virulence of the virus to design an epitope-based polyvalent vaccine against two different strains of EBV, type 1 and 2. Our methodology in this study is nonconventional yet swift to show effective results while designing vaccines.
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27
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Lak S, Janelle V, Djedid A, Boudreau G, Brasey A, Lisi V, Smaani A, Carli C, Busque L, Lavallée VP, Delisle JS. Combined PD-L1 and TIM3 blockade improves expansion of fit human CD8 + antigen-specific T cells for adoptive immunotherapy. Mol Ther Methods Clin Dev 2022; 27:230-245. [PMID: 36320412 PMCID: PMC9593254 DOI: 10.1016/j.omtm.2022.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 09/29/2022] [Indexed: 11/27/2022]
Abstract
Antigen-specific T cell expansion ex vivo followed by adoptive transfer enables targeting of a multitude of microbial and cancer antigens. However, clinical-scale T cell expansion from rare precursors requires repeated stimulation, which may lead to T cell dysfunction and limited therapeutic potential. We used a clinically compliant protocol to expand Epstein-Barr virus (EBV) and Wilms tumor 1 (WT1) antigen-specific CD8+ T cells, and leveraged T cell exhaustion-associated inhibitory receptor blockade to improve T cell expansion. Several inhibitory receptors were expressed early by ex vivo-expanded antigen-specific CD8+ T cells, including PD-1 and TIM3, with co-expression matching evidence of T cell dysfunction as the cultures progressed. Introduction of anti-PD-L1 and anti-TIM3 blockade in combination (but not individually) to the culture led to markedly improved antigen-specific T cell expansion without inducing T cell dysfunction. Single-cell RNA sequencing (RNA-seq) and T cell receptor (TCR) repertoire profiling revealed that double blockade does not impart specific transcriptional programs in T cells or alterations in TCR repertoires. However, combined blockade may affect gene expression in a minority of clonotypes in a donor-specific fashion. We conclude that antigen-specific CD8+ T cell manufacturing can be improved by using TIM3 and PD-L1/PD-1 axis blockade in combination. This approach is readily applicable to several adoptive immunotherapy strategies.
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Affiliation(s)
- Shirin Lak
- Centre de Recherche de L’Hôpital Maisonneuve-Rosemont, 5415 Boul. de L’Assomption, Montréal, QC H1T 2M4, Canada
| | - Valérie Janelle
- Centre de Recherche de L’Hôpital Maisonneuve-Rosemont, 5415 Boul. de L’Assomption, Montréal, QC H1T 2M4, Canada
| | - Anissa Djedid
- Centre de Recherche Du CHU Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Gabrielle Boudreau
- Centre de Recherche de L’Hôpital Maisonneuve-Rosemont, 5415 Boul. de L’Assomption, Montréal, QC H1T 2M4, Canada
| | - Ann Brasey
- Centre de Recherche de L’Hôpital Maisonneuve-Rosemont, 5415 Boul. de L’Assomption, Montréal, QC H1T 2M4, Canada,Biomarker Unit, Centre C3i, 5415 Boul. de L’Assomption, Montréal, QC H1T 2M4, Canada
| | - Véronique Lisi
- Centre de Recherche Du CHU Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Ali Smaani
- Centre de Recherche de L’Hôpital Maisonneuve-Rosemont, 5415 Boul. de L’Assomption, Montréal, QC H1T 2M4, Canada
| | - Cédric Carli
- Centre de Recherche de L’Hôpital Maisonneuve-Rosemont, 5415 Boul. de L’Assomption, Montréal, QC H1T 2M4, Canada
| | - Lambert Busque
- Centre de Recherche de L’Hôpital Maisonneuve-Rosemont, 5415 Boul. de L’Assomption, Montréal, QC H1T 2M4, Canada,Biomarker Unit, Centre C3i, 5415 Boul. de L’Assomption, Montréal, QC H1T 2M4, Canada,Department of Medicine, Université de Montréal, CP 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada,Hematology-Oncology and Cell Therapy Division, Hôpital Maisonneuve-Rosemont, Montréal, QC Canada
| | - Vincent-Philippe Lavallée
- Centre de Recherche Du CHU Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada,Department of Pediatrics, Université de Montréal, Montréal, QC, Canada,Hematology-Oncology Division, CHU Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Jean-Sébastien Delisle
- Centre de Recherche de L’Hôpital Maisonneuve-Rosemont, 5415 Boul. de L’Assomption, Montréal, QC H1T 2M4, Canada,Department of Medicine, Université de Montréal, CP 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada,Hematology-Oncology and Cell Therapy Division, Hôpital Maisonneuve-Rosemont, Montréal, QC Canada,Corresponding author Jean-Sébastien Delisle, MD, FRCPC, PhD, Centre de recherche de l’Hôpital Maisonneuve-Rosemont 5415, Boul de L’Assomption, Montréal, QC, H1T 2M4, Canada.
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Viral infection in hematopoietic stem cell transplantation: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review on the role of cellular therapy in prevention and treatment. Cytotherapy 2022; 24:884-891. [PMID: 35705447 DOI: 10.1016/j.jcyt.2022.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 04/13/2022] [Accepted: 05/22/2022] [Indexed: 11/20/2022]
Abstract
Despite recent advances in the field of HSCT, viral infections remain a frequent causeof morbidity and mortality among HSCT recipients. Adoptive transfer of viral specific T cells has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pretransplant clinical criteria, but milestones of immune reconstitution as well. These factors can better identify those at highest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral specific T cells should be considered for either prophylaxis or second line treatment early after inadequate response to first line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation as well as treatment is challenging in regions where commercial PCR assays and antiviral agents are not readily available.
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29
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HydrAd: A Helper-Dependent Adenovirus Targeting Multiple Immune Pathways for Cancer Immunotherapy. Cancers (Basel) 2022; 14:cancers14112769. [PMID: 35681750 PMCID: PMC9179443 DOI: 10.3390/cancers14112769] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/25/2022] [Accepted: 05/31/2022] [Indexed: 11/29/2022] Open
Abstract
Simple Summary Solid tumors are highly immunosuppressive and develop multiple inhibitory mechanisms that must be targeted simultaneously for successful cancer immunotherapy. Adenoviral vectors are promising cancer gene therapy vectors due to their inherent ability to stimulate multiple immune pathways. Adenoviruses are well characterized, and their genomes are easily manipulated, allowing for therapeutic transgene expression. Oncolytic adenoviruses are engineered to replicate specifically in malignant cells, resulting in cancer cell lysis. However, oncolytic adenoviral vectors have limited transgene capacity. Helper-dependent adenoviral vectors have been developed with the capability of expressing multiple transgenes through removal of all viral coding sequences. We have developed a helper-dependent platform for cancer immunotherapy and demonstrate expression of up to four functional transgenes. This platform allows us to target tumors with specific inhibitory pathways using our library of immunomodulatory transgenes in a mix-and-match approach for a synchronized cancer immunotherapy strategy. Abstract For decades, Adenoviruses (Ads) have been staple cancer gene therapy vectors. Ads are highly immunogenic, making them effective adjuvants. These viruses have well characterized genomes, allowing for substantial modifications including capsid chimerism and therapeutic transgene insertion. Multiple generations of Ad vectors have been generated with reduced or enhanced immunogenicity, depending on their intended purpose, and with increased transgene capacity. The latest-generation Ad vector is the Helper-dependent Ad (HDAd), in which all viral coding sequences are removed from the genome, leaving only the cis-acting ITRs and packaging sequences, providing up to 34 kb of transgene capacity. Although HDAds are replication incompetent, their innate immunogenicity remains intact. Therefore, the HDAd is an ideal cancer gene therapy vector as its infection results in anti-viral immune stimulation that can be enhanced or redirected towards the tumor via transgene expression. Co-infection of tumor cells with an oncolytic Ad and an HDAd results in tumor cell lysis and amplification of HDAd-encoded transgene expression. Here, we describe an HDAd-based cancer gene therapy expressing multiple classes of immunomodulatory molecules to simultaneously stimulate multiple axes of immune pathways: the HydrAd. Overall, the HydrAd platform represents a promising cancer immunotherapy agent against complex solid tumors.
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The generation and application of antigen-specific T cell therapies for cancer and viral-associated disease. Mol Ther 2022; 30:2130-2152. [PMID: 35149193 PMCID: PMC9171249 DOI: 10.1016/j.ymthe.2022.02.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/27/2021] [Accepted: 02/03/2022] [Indexed: 11/23/2022] Open
Abstract
Immunotherapy with antigen-specific T cells is a promising, targeted therapeutic option for patients with cancer as well as for immunocompromised patients with virus infections. In this review, we characterize and compare current manufacturing protocols for the generation of T cells specific to viral and non-viral tumor-associated antigens. Specifically, we discuss: (1) the different methodologies to expand virus-specific T cell and non-viral tumor-associated antigen-specific T cell products, (2) an overview of the immunological principles involved when developing such manufacturing protocols, and (3) proposed standardized methodologies for the generation of polyclonal, polyfunctional antigen-specific T cells irrespective of donor source. Ex vivo expanded cells have been safely administered to treat numerous patients with virus-associated malignancies, hematologic malignancies, and solid tumors. Hence, we have performed a comprehensive review of the clinical trial results evaluating the safety, feasibility, and efficacy of these products in the clinic. In summary, this review seeks to provide new insights regarding antigen-specific T cell technology to benefit a rapidly expanding T cell therapy field.
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Chen S, Bin Abdul Rahim AA, Wang WW, Cheong R, Prabhu AV, Tan JZY, Naing MW, Toh HC, Liu D. In-situ scalable manufacturing of Epstein-Barr virus-specific T-cells using bioreactor with an expandable culture area (BECA). Sci Rep 2022; 12:7045. [PMID: 35487951 PMCID: PMC9054749 DOI: 10.1038/s41598-022-11015-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 04/15/2022] [Indexed: 11/09/2022] Open
Abstract
The ex-vivo expansion of antigen-specific T-cells for adoptive T-cell immunotherapy requires active interaction between T-cells and antigen-presenting cells therefore culture density and environment become important variables to control. Maintenance of culture density in a static environment is traditionally performed by the expansion of the culture area through splitting of culture from a single vessel into multiple vessels-a highly laborious process. This study aims to validate the use and efficacy of a novel bioreactor, bioreactor with an expandable culture area-dual chamber (BECA-D), that was designed and developed with a cell chamber with expandable culture area (12-108 cm2) and a separate media chamber to allow for in-situ scaling of culture with maintenance of optimum culture density and improved nutrient and gas exchange while minimizing disturbance to the culture. The performance of BECA-D in the culture of Epstein-Barr virus-specific T-cells (EBVSTs) was compared to the 24-well plate. BECA-D had 0.9-9.7 times the average culture yield of the 24-well plates across 5 donor sets. BECA-D was able to maintain the culture environment with relatively stable glucose and lactate levels as the culture expanded. This study concludes that BECA-D can support the culture of ex-vivo EBVSTs with lower manufacturing labour and time requirements compared to the use of the 24-well plate. BECA-D and its adaptation into a closed system with an automated platform (currently being developed) provides cell therapy manufacturers and developers with a closed scale-out solution to producing adoptive cell therapy for clinical use.
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Affiliation(s)
- Sixun Chen
- Biomanufacturing Technology, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Singapore, 138668, Singapore
| | - Ahmad Amirul Bin Abdul Rahim
- Biomanufacturing Technology, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Singapore, 138668, Singapore
| | - Who-Whong Wang
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Cres, Singapore, 169610, Singapore
| | - Rachael Cheong
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Cres, Singapore, 169610, Singapore
| | - Akshaya V Prabhu
- Biomanufacturing Technology, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Singapore, 138668, Singapore
| | - Jerome Zu Yao Tan
- Biomanufacturing Technology, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Singapore, 138668, Singapore.,Interdisciplinary Graduate Programme, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, Singapore
| | - May Win Naing
- Singapore Institute of Manufacturing Technology (SIMTech), A*STAR, 2 Fusionopolis Way, Singapore, 138634, Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Cres, Singapore, 169610, Singapore
| | - Dan Liu
- Biomanufacturing Technology, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Singapore, 138668, Singapore.
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Enhancement of Antiviral T-Cell Responses by Vitamin C Suggests New Strategies to Improve Manufacturing of Virus-Specific T Cells for Adoptive Immunotherapy. BIOLOGY 2022; 11:biology11040536. [PMID: 35453735 PMCID: PMC9032103 DOI: 10.3390/biology11040536] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/14/2022] [Accepted: 03/28/2022] [Indexed: 11/17/2022]
Abstract
Allogeneic and autologous transplantation of hematopoietic stem cells (HSCT) are being routinely used to treat patients with leukemia and lymphoma. Due to the required immunosuppression after stem cell transplantation, infection and reactivation by viruses are life-threatening complications. In recent years, adoptive transfer using virus-specific T cells (VSTs) has emerged as alternative to conventional therapies. Since vitamins are described to influence the immune system and its cellular components, the aim of this study was to examine whether vitamins modulate VST function and thereby enable an improvement of therapy. For that, we investigated the impact of vitamin C and D on the functionality of cytomegalovirus (CMV)-specific T cells isolated from CMV-seropositive healthy donors. We were able to show that vitamin C increases the expansion and activation state of CMV-specific T cells, and an increased influence of vitamin C was observed on cells isolated from male donors and donors above 40 years of age. A higher frequency of the terminally differentiated effector memory CD8+ T-cell population in these donors indicates a connection between these cells and the enhanced response to vitamin C. Thus, here we provide insights into the impact of vitamin C on cytotoxic T cells as well as possible additional selection criteria and strategies to improve VST functionality.
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Cellular therapies for the treatment and prevention of SARS-CoV-2 infection. Blood 2022; 140:208-221. [PMID: 35240679 PMCID: PMC8896869 DOI: 10.1182/blood.2021012249] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/01/2022] [Indexed: 12/15/2022] Open
Abstract
Patients with blood disorders who are immune suppressed are at increased risk for infection with severe acute respiratory syndrome coronavirus 2. Sequelae of infection can include severe respiratory disease and/or prolonged duration of viral shedding. Cellular therapies may protect these vulnerable patients by providing antiviral cellular immunity and/or immune modulation. In this recent review of the field, phase 1/2 trials evaluating adoptive cellular therapies with virus-specific T cells or natural killer cells are described along with trials evaluating the safety, feasibility, and preliminary efficacy of immune modulating cellular therapies including regulatory T cells and mesenchymal stromal cells. In addition, the immunologic basis for these therapies is discussed.
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Harada S, Ando M, Ando J, Ishii M, Yamaguchi T, Yamazaki S, Toyota T, Ohara K, Ohtaka M, Nakanishi M, Shin C, Ota Y, Nakashima K, Ohshima K, Imai C, Nakazawa Y, Nakauchi H, Komatsu N. Dual-antigen targeted iPSC-derived chimeric antigen receptor-T cell therapy for refractory lymphoma. Mol Ther 2022; 30:534-549. [PMID: 34628050 PMCID: PMC8821952 DOI: 10.1016/j.ymthe.2021.10.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 07/04/2021] [Accepted: 09/30/2021] [Indexed: 02/04/2023] Open
Abstract
We generated dual-antigen receptor (DR) T cells from induced pluripotent stem cells (iPSCs) to mitigate tumor antigen escape. These cells were engineered to express a chimeric antigen receptor (CAR) for the antigen cell surface latent membrane protein 1 (LMP1; LMP1-CAR) and a T cell receptor directed to cell surface latent membrane protein 2 (LMP2), in association with human leucocyte antigen A24, to treat therapy-refractory Epstein-Barr virus-associated lymphomas. We introduced LMP1-CAR into iPSCs derived from LMP2-specific cytotoxic T lymphocytes (CTLs) to generate rejuvenated CTLs (rejTs) active against LMP1 and LMP2, or DRrejTs. All DRrejT-treated mice survived >100 days. Furthermore, DRrejTs rejected follow-up inocula of lymphoma cells, demonstrating that DRrejTs persisted long-term. We also demonstrated that DRrejTs targeting CD19 and LMP2 antigens exhibited a robust tumor suppressive effect and conferred a clear survival advantage. Co-operative antitumor effect and in vivo persistence, with unlimited availability of DRrejT therapy, will provide powerful and sustainable T cell immunotherapy.
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Affiliation(s)
- Sakiko Harada
- Department of Hematology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Miki Ando
- Department of Hematology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; Division of Stem Cell Therapy, Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
| | - Jun Ando
- Department of Hematology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Midori Ishii
- Department of Hematology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Tomoyuki Yamaguchi
- Division of Stem Cell Therapy, Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Satoshi Yamazaki
- Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Laboratory of Stem Cell Therapy Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
| | - Tokuko Toyota
- Department of Hematology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Kazuo Ohara
- Department of Hematology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Manami Ohtaka
- TOKIWA-Bio, Inc., Tsukuba Center, Ibaraki 305-0047, Japan
| | | | - Chansu Shin
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Yasunori Ota
- Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Kazutaka Nakashima
- Department of Pathology, School of Medicine, Kurume University, Fukuoka 830-0011, Japan
| | - Koichi Ohshima
- Department of Pathology, School of Medicine, Kurume University, Fukuoka 830-0011, Japan
| | - Chihaya Imai
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Yozo Nakazawa
- Department of Pediatrics, Shinsyu University School of Medicine, Nagano 390-0802, Japan
| | - Hiromitsu Nakauchi
- Division of Stem Cell Therapy, Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305-5461, USA.
| | - Norio Komatsu
- Department of Hematology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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Conway SR, Lazarski CA, Field NE, Jensen-Wachspress M, Lang H, Kankate V, Durkee-Shock J, Kinoshita H, Suslovic W, Webber K, Smith K, Cohen JI, Burbelo PD, Zhang A, Teach SJ, Ibeh T, Delaney M, DeBiasi RL, Keller MD, Bollard CM. SARS-CoV-2-Specific T Cell Responses Are Stronger in Children With Multisystem Inflammatory Syndrome Compared to Children With Uncomplicated SARS-CoV-2 Infection. Front Immunol 2022; 12:793197. [PMID: 35116027 PMCID: PMC8803660 DOI: 10.3389/fimmu.2021.793197] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 12/22/2021] [Indexed: 12/21/2022] Open
Abstract
Background Despite similar rates of infection, adults and children have markedly different morbidity and mortality related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Compared to adults, children have infrequent severe manifestations of acute infection but are uniquely at risk for the rare and often severe Multisystem Inflammatory Syndrome in Children (MIS-C) following infection. We hypothesized that these differences in presentation are related to differences in the magnitude and/or antigen specificity of SARS-CoV-2-specific T cell (CST) responses between adults and children. We therefore set out to measure the CST response in convalescent adults versus children with and without MIS-C following SARS-CoV-2 infection. Methods CSTs were expanded from blood collected from convalescent children and adults post SARS-CoV-2 infection and evaluated by intracellular flow cytometry, surface markers, and cytokine production following stimulation with SARS-CoV-2-specific peptides. Presence of serum/plasma antibody to spike and nucleocapsid was measured using the luciferase immunoprecipitation systems (LIPS) assay. Findings Twenty-six of 27 MIS-C patients, 7 of 8 non-MIS-C convalescent children, and 13 of 14 adults were seropositive for spike and nucleocapsid antibody. CST responses in MIS-C patients were significantly higher than children with uncomplicated SARS-CoV-2 infection, but weaker than CST responses in convalescent adults. Interpretation Age-related differences in the magnitude of CST responses suggest differing post-infectious immunity to SARS-CoV-2 in children compared to adults post uncomplicated infection. Children with MIS-C have CST responses that are stronger than children with uncomplicated SARS-CoV-2 infection and weaker than convalescent adults, despite near uniform seropositivity.
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Affiliation(s)
- Susan R. Conway
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
- Division of Critical Care Medicine, Children’s National Hospital, Washington, DC, United States
- Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Christopher A. Lazarski
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
| | - Naomi E. Field
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
| | - Mariah Jensen-Wachspress
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
| | - Haili Lang
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
| | - Vaishnavi Kankate
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
| | - Jessica Durkee-Shock
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
- Laboratory of Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Hannah Kinoshita
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
- Division of Hematology and Oncology, Children’s National Hospital, Washington, DC, United States
| | - William Suslovic
- Division of Pathology and Laboratory Medicine, Children’s National Hospital, Washington, DC, United States
| | - Kathleen Webber
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
| | - Karen Smith
- Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
- Department of Pediatrics, Children’s National Hospital, Washington, DC, United States
| | - Jeffrey I. Cohen
- Laboratory of Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Peter D. Burbelo
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States
| | - Anqing Zhang
- Division of Biostatistics and Study Methodology, Children’s National Hospital, Washington, DC, United States
| | - Stephen J. Teach
- Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
- Center for Translational Research, Children’s National Hospital, Washington, DC, United States
| | - Trisha Ibeh
- Center for Translational Research, Children’s National Hospital, Washington, DC, United States
| | - Meghan Delaney
- Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
- Division of Pathology and Laboratory Medicine, Children’s National Hospital, Washington, DC, United States
| | - Roberta L. DeBiasi
- Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
- Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
- Division of Infectious Diseases, Children’s National Hospital, Washington, DC, United States
| | - Michael D. Keller
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
- Division of Allergy and Immunology, Children’s National Hospital, Washington, DC, United States
- GW Cancer Center, George Washington University, Washington, DC, United States
| | - Catherine M. Bollard
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC, United States
- GW Cancer Center, George Washington University, Washington, DC, United States
- *Correspondence: Catherine M. Bollard,
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Cytomegalovirus and other herpesviruses after hematopoietic cell and solid organ transplantation: From antiviral drugs to virus-specific T cells. Transpl Immunol 2022; 71:101539. [PMID: 35051589 DOI: 10.1016/j.trim.2022.101539] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 12/13/2022]
Abstract
Herpesviruses can either cause primary infection or may get reactivated after both hematopoietic cell and solid organ transplantations. In general, viral infections increase post-transplant morbidity and mortality. Prophylactic, preemptive, or therapeutically administered antiviral drugs may be associated with serious side effects and may induce viral resistance. Virus-specific T cells represent a valuable addition to antiviral treatment, with high rates of response and minimal side effects. Even low numbers of virus-specific T cells manufactured by direct selection methods can reconstitute virus-specific immunity after transplantation and control viral replication. Virus-specific T cells belong to the advanced therapy medicinal products, and their production is regulated by appropriate legislation; also, strict safety regulations are required to minimize their side effects.
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Gotti E, Tettamanti S, Zaninelli S, Cuofano C, Cattaneo I, Rotiroti MC, Cribioli S, Alzani R, Rambaldi A, Introna M, Golay J. Optimization of therapeutic T cell expansion in G-Rex device and applicability to large-scale production for clinical use. Cytotherapy 2022; 24:334-343. [DOI: 10.1016/j.jcyt.2021.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/02/2021] [Accepted: 11/02/2021] [Indexed: 02/02/2023]
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Kaiser D, Otto NM, McCallion O, Hoffmann H, Zarrinrad G, Stein M, Beier C, Matz I, Herschel M, Hester J, Moll G, Issa F, Reinke P, Roemhild A. Freezing Medium Containing 5% DMSO Enhances the Cell Viability and Recovery Rate After Cryopreservation of Regulatory T Cell Products ex vivo and in vivo. Front Cell Dev Biol 2021; 9:750286. [PMID: 34926446 PMCID: PMC8677839 DOI: 10.3389/fcell.2021.750286] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/05/2021] [Indexed: 12/29/2022] Open
Abstract
Cell therapies have significant therapeutic potential in diverse fields including regenerative medicine, transplantation tolerance, and autoimmunity. Within these fields, regulatory T cells (Treg) have been deployed to ameliorate aberrant immune responses with great success. However, translation of the cryopreservation strategies employed for other cell therapy products, such as effector T cell therapies, to Treg therapies has been challenging. The lack of an optimized cryopreservation strategy for Treg products presents a substantial obstacle to their broader application, particularly as administration of fresh cells limits the window available for sterility and functional assessment. In this study, we aimed to develop an optimized cryopreservation strategy for our CD4+CD25+Foxp3+ Treg clinical product. We investigate the effect of synthetic or organic cryoprotectants including different concentrations of DMSO on Treg recovery, viability, phenotype, cytokine production, suppressive capacity, and in vivo survival following GMP-compliant manufacture. We additionally assess the effect of adding the extracellular cryoprotectant polyethylene glycol (PEG), or priming cellular expression of heat shock proteins as strategies to improve viability. We find that cryopreservation in serum-free freezing medium supplemented with 10% human serum albumin and 5% DMSO facilitates improved Treg recovery and functionality and supports a reduced DMSO concentration in Treg cryopreservation protocols. This strategy may be easily incorporated into clinical manufacture protocols for future studies.
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Affiliation(s)
- Daniel Kaiser
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Natalie Maureen Otto
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver McCallion
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Henrike Hoffmann
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Ghazaleh Zarrinrad
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Maik Stein
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Carola Beier
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Isabell Matz
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Marleen Herschel
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Joanna Hester
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Guido Moll
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Fadi Issa
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Petra Reinke
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Andy Roemhild
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
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Beyond antivirals: virus-specific T-cell immunotherapy for BK virus haemorrhagic cystitis and JC virus progressive multifocal leukoencephalopathy. Curr Opin Infect Dis 2021; 34:627-634. [PMID: 34751182 DOI: 10.1097/qco.0000000000000794] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW The clinical manifestations of the polyomaviruses BK and JC in immunocompromised patients include BK virus (BKV) induced haemorrhagic cystitis and nephropathy, and JC virus (JCV) associated progressive multifocal leukoencephalopathy (PML) and are typically a consequence of impaired adaptive immunity in the host. To date, little clinical success has been achieved with antiviral agents or other drug therapies to treat these conditions. Here we review the methods and outcomes of the most recent clinical studies utilising adoptive immunotherapy with BK and/or JC virus-specific T-cells (VST) as either prophylaxis or treatment alternatives. RECENT FINDINGS In the last 12-18 months, several clinical trials have been published in the post-haemopoietic stem cell transplant (HSCT) setting showing good clinical success with the use of VST for treatment of BK viremia ± haemorrhagic cystitis. Between 82 and 100% clinical response has been observed in haemorrhagic cystitis using either third-party or donor-derived VST. The therapy was well tolerated with few cases of graft versus host disease in HSCT recipients, but immune mediated renal allograft loss was observed in one renal transplant recipient. Studies using BKV/JCV VST to treat PML are hindered by few patients who are sufficiently stable to receive VST. In a condition that otherwise carries such poor prognosis, VST were associated with clearance of JC virus, clinical and radiological improvement in some patients. Immune reconstitution inflammatory syndrome was a noted adverse event. SUMMARY Restoration of BK and JC virus immunity using VST immunotherapy has shown good clinical outcomes in BKV associated infections. Further evaluation with the administration of VST earlier in the course of disease is warranted for the treatment of BKV associated nephropathy in renal allograft and in JCV PML. In both indications, larger cohorts and standardisation of dosing and outcome measures would be of benefit.
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Wang X, Diamond DJ, Forman SJ, Nakamura R. Development of CMV-CD19 bi-specific CAR T cells with post-infusion in vivo boost using an anti-CMV vaccine. Int J Hematol 2021; 114:544-553. [PMID: 34561840 PMCID: PMC8475363 DOI: 10.1007/s12185-021-03215-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/21/2021] [Accepted: 09/01/2021] [Indexed: 11/25/2022]
Abstract
Adoptive transfer of in vitro expanded, chimeric antigen receptor (CAR)-redirected CD19-specific T cells can induce dramatic disease regression in patients with leukemia and lymphomas. However, the full potential of this emerging modality is hampered in some cancer settings by a significant rate of therapeutic failure arising from the attenuated engraftment and persistence of CAR-redirected T cells, and tumor relapse following adoptive transfer. Here, we discuss an advanced strategy that facilitates post-infusion in vivo boosting of CAR T cells via CMV vaccination, to mediate durable remission of B cell malignancies by engrafting a CAR molecule onto a CMV-specific T cell. We also discuss a feasible and unique platform for the generation of the CMV-CD19CAR T cells for clinical application. This new approach would overcome multiple challenges in current CAR T cell technology including: short T cell persistence, limited duration of response, and inability to re-stimulate T cells after relapse or persistent disease.
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Affiliation(s)
- Xiuli Wang
- Department of Hematology/HCT, City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Don J Diamond
- Department of Hematology/HCT, City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Stephen J Forman
- Department of Hematology/HCT, City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Ryotaro Nakamura
- Department of Hematology/HCT, City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
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Cytomegalovirus Infections in Children with Primary and Secondary Immune Deficiencies. Viruses 2021; 13:v13102001. [PMID: 34696432 PMCID: PMC8538792 DOI: 10.3390/v13102001] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/30/2021] [Accepted: 10/02/2021] [Indexed: 12/15/2022] Open
Abstract
Cytomegalovirus (CMV) is a human herpes virus that causes significant morbidity and mortality in immunosuppressed children. CMV primary infection causes a clinically mild disease in healthy children, usually in early childhood; the virus then utilises several mechanisms to establish host latency, which allows for periodic reactivation, particularly when the host is immunocompromised. It is this reactivation that is responsible for the significant morbidity and mortality in immunocompromised children. We review CMV infection in the primary immunodeficient host, including early identification of these infants by newborn screening to allow for CMV infection prevention strategies. Furthermore, clinical CMV is discussed in the context of children treated with secondary immunodeficiency, particularly paediatric cancer patients and children undergoing haematopoietic stem cell transplant (HSCT). Treatments for CMV are highlighted and include CMV immunotherapy.
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Daly S, O’Sullivan A, MacLoughlin R. Cellular Immunotherapy and the Lung. Vaccines (Basel) 2021; 9:1018. [PMID: 34579255 PMCID: PMC8473388 DOI: 10.3390/vaccines9091018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023] Open
Abstract
The new era of cellular immunotherapies has provided state-of-the-art and efficient strategies for the prevention and treatment of cancer and infectious diseases. Cellular immunotherapies are at the forefront of innovative medical care, including adoptive T cell therapies, cancer vaccines, NK cell therapies, and immune checkpoint inhibitors. The focus of this review is on cellular immunotherapies and their application in the lung, as respiratory diseases remain one of the main causes of death worldwide. The ongoing global pandemic has shed a new light on respiratory viruses, with a key area of concern being how to combat and control their infections. The focus of cellular immunotherapies has largely been on treating cancer and has had major successes in the past few years. However, recent preclinical and clinical studies using these immunotherapies for respiratory viral infections demonstrate promising potential. Therefore, in this review we explore the use of multiple cellular immunotherapies in treating viral respiratory infections, along with investigating several routes of administration with an emphasis on inhaled immunotherapies.
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Affiliation(s)
- Sorcha Daly
- College of Medicine, Nursing & Health Sciences, National University of Ireland, H91 TK33 Galway, Ireland;
| | - Andrew O’Sullivan
- Research and Development, Science and Emerging Technologies, Aerogen Limited, Galway Business Park, H91 HE94 Galway, Ireland;
| | - Ronan MacLoughlin
- Research and Development, Science and Emerging Technologies, Aerogen Limited, Galway Business Park, H91 HE94 Galway, Ireland;
- School of Pharmacy and Pharmaceutical Sciences, Trinity College, D02 PN40 Dublin, Ireland
- School of Pharmacy & Biomolecular Sciences, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland
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Ishii M, Ando J, Yamazaki S, Toyota T, Ohara K, Furukawa Y, Suehara Y, Nakanishi M, Nakashima K, Ohshima K, Nakauchi H, Ando M. iPSC-Derived Neoantigen-Specific CTL Therapy for Ewing Sarcoma. Cancer Immunol Res 2021; 9:1175-1186. [PMID: 34385178 DOI: 10.1158/2326-6066.cir-21-0193] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/22/2021] [Accepted: 08/09/2021] [Indexed: 11/16/2022]
Abstract
The prognosis of Ewing sarcoma caused by EWS/FLI1 fusion is poor, especially after metastasis. Although therapy with CTLs targeted against altered EWS/FLI1 sequences at the gene break/fusion site may be effective, CTLs generated from peripheral blood are often exhausted because of continuous exposure to tumor antigens. We addressed this by generating induced pluripotent stem cell (iPSC)-derived functionally rejuvenated CTLs (rejT) directed against the neoantigen encoded by the EWS/FLI1 fusion gene. In this study, we examined the antitumor effects of EWS/FLI1-rejTs against Ewing sarcoma. The altered amino acid sequence at the break/fusion point of EWS/FLI1, when presented as a neoantigen, evokes an immune response that targets EWS/FLI1 + sarcoma. Although the frequency of generated EWS/FLI1-specific CTLs was only 0.003%, we successfully established CTL clones from a healthy donor. We established iPSCs from a EWS/FLI1-specific CTL clone and redifferentiated them into EWS/FLI1-specific rejTs. To evaluate cytotoxicity, we cocultured EWS/FLI1-rejTs with Ewing sarcoma cell lines. EWS/FLI1-rejTs rapidly and continuously suppressed the proliferation of Ewing sarcoma for >40 hours. Using a Ewing sarcoma xenograft mouse model, we verified the antitumor effect of EWS/FLI1-rejTs via imaging, and EWS/FLI1-rejTs conferred a statistically significant survival advantage. "Off-the-shelf" therapy is less destructive and disruptive than chemotherapy, and radiation is always desirable, particularly in adolescents, whom Ewing sarcoma most often affects. Thus, EWS/FLI1-rejTs targeting a Ewing sarcoma neoantigen could be a promising new therapeutic tool.
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Affiliation(s)
- Midori Ishii
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
- Department of Orthopaedic Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Jun Ando
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
- Department of Blood Transfusion Medicine and Stem Cell Regulation, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Satoshi Yamazaki
- Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
- Laboratory of Stem Cell Therapy, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Tokuko Toyota
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Kazuo Ohara
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Yoshiki Furukawa
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Yoshiyuki Suehara
- Department of Orthopaedic Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Mahito Nakanishi
- TOKIWA-Bio, Inc., Tsukuba Center Inc. (TCI), Tsukuba, Ibaraki, Japan
| | - Kazutaka Nakashima
- Department of Pathology, School of Medicine, Kurume University, Kurume City, Fukuoka, Japan
| | - Koichi Ohshima
- Department of Pathology, School of Medicine, Kurume University, Kurume City, Fukuoka, Japan
| | - Hiromitsu Nakauchi
- Division of Stem Cell Therapy, Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, School of Medicine, Stanford, California
| | - Miki Ando
- Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
- Division of Stem Cell Therapy, Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
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Papadopoulou A, Koukoulias K, Alvanou M, Papadopoulos VK, Bousiou Z, Kalaitzidou V, Kika FS, Papalexandri A, Mallouri D, Batsis I, Sakellari I, Anagnostopoulos A, Yannaki E. Patient risk stratification and tailored clinical management of post-transplant CMV-, EBV-, and BKV-infections by monitoring virus-specific T-cell immunity. EJHAEM 2021; 2:428-439. [PMID: 35844677 PMCID: PMC9175754 DOI: 10.1002/jha2.175] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/09/2021] [Accepted: 02/12/2021] [Indexed: 12/13/2022]
Abstract
Background Despite routine post-transplant viral monitoring and pre-emptive therapy, viral infections remain a major cause of allogeneic hematopoietic cell transplantation-related morbidity and mortality. Objective We here aimed to prospectively assess the kinetics and the magnitude of cytomegalovirus-(CMV), Epstein Barr virus-(EBV), and BK virus-(BKV)-specific T cell responses post-transplant and evaluate their role in guiding therapeutic decisions by patient risk-stratification. Study design The tri-virus-specific immune recovery was assessed by Elispot, in 50 consecutively transplanted patients, on days +20, +30, +60, +100, +150, +200 post-transplant and in case of reactivation, weekly for 1 month. Results The great majority of the patients experienced at least one reactivation, while over 40% of them developed multiple reactivations from more than one of the tested viruses, especially those transplanted from matched or mismatched unrelated donors. The early reconstitution of virus-specific immunity (day +20), favorably correlated with transplant outcomes. Εxpanding levels of CMV-, EBV-, and BKV-specific T cells (VSTs) post-reactivation coincided with decreasing viral load and control of infection. Certain cut-offs of absolute VST numbers or net VST cell expansion post-reactivation were determined, above which, patients with CMV or BKV reactivation had >90% probability of complete response (CR). Conclusion Immune monitoring of virus-specific T-cell reconstitution post-transplant may allow risk-stratification of virus reactivating patients and enable patient-tailored treatment. The identification of individuals with high probability of CR will minimize unnecessary overtreatment and drug-associated toxicity while allowing candidates for pre-emptive intervention with adoptive transfer of VSTs to be appropriately selected.
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Affiliation(s)
- Anastasia Papadopoulou
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Kiriakos Koukoulias
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
- Department of Genetics, Development and Molecular Biology, School of BiologyAristotle University of ThessalonikiThessalonikiGreece
| | - Maria Alvanou
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | | | - Zoe Bousiou
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Vasiliki Kalaitzidou
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Fotini S. Kika
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Apostolia Papalexandri
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Despina Mallouri
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Ioannis Batsis
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Ioanna Sakellari
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Achilles Anagnostopoulos
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Evangelia Yannaki
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
- Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
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El Fiky A, Ibenana L, Anderson R, Hare JM, Khan A, Gee AP, Rooney C, McKenna DH, Gold J, Kelley L, Lundberg MS, Welniak LA, Lindblad R. The National Heart, Lung, and Blood Institute-funded Production Assistance for Cellular Therapies (PACT) program: Eighteen years of cell therapy. Clin Transl Sci 2021; 14:2099-2110. [PMID: 34286927 PMCID: PMC8604220 DOI: 10.1111/cts.13102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/08/2021] [Accepted: 05/24/2021] [Indexed: 11/29/2022] Open
Abstract
The Production Assistance for Cellular Therapies (PACT) Program, is funded and supported by the US Department of Health and Human Services’ National Institutes of Health (NIH) National Heart Lung and Blood Institute (NHLBI) to advance development of somatic cell and genetically modified cell therapeutics in the areas of heart, lung, and blood diseases. The program began in 2003, continued under two competitive renewals, and ended June 2021. PACT has supported cell therapy product manufacturing, investigational new drug enabling preclinical studies, and translational services, and has provided regulatory assistance for candidate cell therapy products that may aid in the repair and regeneration of damaged/diseased cells, tissues, and organs. PACT currently supports the development of novel cell therapies through five cell processing facilities. These facilities offer manufacturing processes, analytical development, technology transfer, process scale‐up, and preclinical development expertise necessary to produce cell therapy products that are compliant with Good Laboratory Practices, current Good Manufacturing Practices, and current Good Tissue Practices regulations. The Emmes Company, LLC, serves as the Coordinating Center and assists with the management and coordination of PACT and its application submission and review process. This paper discusses the impact and accomplishments of the PACT program on the cell therapy field and its evolution over the duration of the program. It highlights the work that has been accomplished and provides a foundation to build future programs with similar goals to advance cellular therapeutics in a coordinated and centralized programmatic manner to support unmet medical needs within NHLBI purview.
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Affiliation(s)
| | | | | | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Aisha Khan
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Adrian P Gee
- Center For Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - Cliona Rooney
- Center For Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - David H McKenna
- Molecular and Cellular Therapeutics, University of Minnesota, Saint Paul, Minnesota, USA
| | - Joseph Gold
- Center for Biomedicine and Genetics, City of Hope, Duarte, California, USA
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Zhang C, Tan Q, Li S, Shen L, Zhang J, Liu Y, Yang W, Lu Z. Induction of EBV latent membrane protein-2A (LMP2A)-specific T cells and construction of individualized TCR-engineered T cells for EBV-associated malignancies. J Immunother Cancer 2021; 9:jitc-2021-002516. [PMID: 34210819 PMCID: PMC8252876 DOI: 10.1136/jitc-2021-002516] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2021] [Indexed: 12/05/2022] Open
Abstract
Background Latent membrane protein-2A (LMP2A)-specific TCR-engineered T cells could be a promising treatment approach to Epstein–Barr virus-associated malignancies. However, previous studies mainly reported LMP2A-reactive TCRs only focusing on specific HLA subtypes and corresponding epitopes, and thus, they were only suitable for patients with specific HLA. Methods Due to hugely varied HLA subtypes and presented LMP2A epitopes in different individuals, our study attempted to develop an individualized approach, based on the weekly in vitro stimulation of peripheral T cells for 2 weeks with autologous dendritic cells (DCs) pulsed with a pool of LMP2A peptides covering LMP2A whole protein and combination analysis of high throughput TCRβ sequencing of prestimulated and poststimulated T cells and single-cell TCR sequencing of poststimulated T cells, and to identify LMP2A-specific TCRs of which poststimulated frequencies significantly increased than corresponding prestimulated frequencies. Results Following this approach, multiple LMP2A-reactive TCRs were identified, optimized and cloned into lentiviral vector, and then transduced into peripheral T cells. These engineerd T cells were demonstrated to specifically recognize the LMP2A presented by autologous DCs and lymphoblastoid cell lines in vitro and in vivo. Conclusions This approach provides an efficient procedure to isolate individualized LMP2A-specific TCRs for basic and translational research, as well as for clinical applications.
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Affiliation(s)
- Chaoting Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Qin Tan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, China
| | - Shance Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Luyan Shen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jingtao Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ying Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, China
| | - Wenjun Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, China .,Key Laboratory of Fertility Preservation and Maintenance, School of Basic Medicine and the General Hospital, Ningxia Medical University, Yinchuan, China
| | - Zheming Lu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, China
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Shahid S, Prockop SE. Epstein-Barr virus-associated post-transplant lymphoproliferative disorders: beyond chemotherapy treatment. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:646-664. [PMID: 34485854 PMCID: PMC8415721 DOI: 10.20517/cdr.2021.34] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/10/2021] [Accepted: 05/19/2021] [Indexed: 12/30/2022]
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication of both allogeneic solid organ (SOT) and hematopoietic cell transplantation (HCT). The histology of PTLD ranges from benign polyclonal lymphoproliferation to a lesion indistinguishable from classic monoclonal lymphoma. Most commonly, PTLDs are Epstein-Barr virus (EBV) positive and result from loss of immune surveillance over EBV. Treatment for PTLD differs from the treatment for typical non-Hodgkin lymphoma because prognostic factors are different, resistance to treatment is unique, and there are specific concerns for organ toxicity. While recipients of HCT have a limited time during which they are at risk for this complication, recipients of SOT have a lifelong requirement for immunosuppression, so approaches that limit compromising or help restore immune surveillance are of high interest. Furthermore, while EBV-positive and EBV-negative PTLDs are not intrinsically resistant to chemotherapy, the poor tolerance of chemotherapy in the post-transplant setting makes it essential to minimize potential treatment-related toxicities and explore alternative treatment algorithms. Therefore, reduced-toxicity approaches such as single-agent CD20 monoclonal antibodies or bortezomib, reduced dosing of standard chemotherapeutic agents, and non-chemotherapy-based approaches such as cytotoxic T cells have all been explored. Here, we review the chemotherapy and non-chemotherapy treatment landscape for PTLD.
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Affiliation(s)
| | - Susan E. Prockop
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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Karavalakis G, Yannaki E, Papadopoulou A. Reinforcing the Immunocompromised Host Defense against Fungi: Progress beyond the Current State of the Art. J Fungi (Basel) 2021; 7:jof7060451. [PMID: 34204025 PMCID: PMC8228486 DOI: 10.3390/jof7060451] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/11/2022] Open
Abstract
Despite the availability of a variety of antifungal drugs, opportunistic fungal infections still remain life-threatening for immunocompromised patients, such as those undergoing allogeneic hematopoietic cell transplantation or solid organ transplantation. Suboptimal efficacy, toxicity, development of resistant variants and recurrent episodes are limitations associated with current antifungal drug therapy. Adjunctive immunotherapies reinforcing the host defense against fungi and aiding in clearance of opportunistic pathogens are continuously gaining ground in this battle. Here, we review alternative approaches for the management of fungal infections going beyond the state of the art and placing an emphasis on fungus-specific T cell immunotherapy. Harnessing the power of T cells in the form of adoptive immunotherapy represents the strenuous protagonist of the current immunotherapeutic approaches towards combating invasive fungal infections. The progress that has been made over the last years in this field and remaining challenges as well, will be discussed.
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Affiliation(s)
- Georgios Karavalakis
- Hematology Department-Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, 57010 Thessaloniki, Greece; (G.K.); (E.Y.)
| | - Evangelia Yannaki
- Hematology Department-Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, 57010 Thessaloniki, Greece; (G.K.); (E.Y.)
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Anastasia Papadopoulou
- Hematology Department-Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, 57010 Thessaloniki, Greece; (G.K.); (E.Y.)
- Correspondence: ; Tel.: +30-2313-307-693; Fax: +30-2313-307-521
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Wang X, Patel SA, Haddadin M, Cerny J. Post-allogeneic hematopoietic stem cell transplantation viral reactivations and viremias: a focused review on human herpesvirus-6, BK virus and adenovirus. Ther Adv Infect Dis 2021; 8:20499361211018027. [PMID: 34104434 PMCID: PMC8155777 DOI: 10.1177/20499361211018027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/27/2021] [Indexed: 12/30/2022] Open
Abstract
Human cytomegalovirus and Epstein-Barr virus have been recognized as potential drivers of morbidity and mortality of patients undergoing allogeneic stem cell transplantation for years. Specific protocols for monitoring, prophylaxis and pre-emptive therapy are in place in many transplant settings. In this review, we focus on the next three most frequent viruses, human herpesvirus-6, BK virus and adenovirus, causing reactivation and/or viremia after allogeneic transplant, which are increasingly detected in patients in the post-transplant period owing to emerging techniques of molecular biology, recipients' characteristics, treatment modalities used for conditioning and factors related donors or stem cell source. Given the less frequent detection of an illness related to these viruses, there are often no specific protocols in place for the management of affected patients. While some patients develop significant morbidity (generally older), others may not need therapy at all (generally younger or children). Furthermore, some of the antiviral therapies used are potentially toxic. With the addition of increased risk of secondary infections, risk of graft failure or increased risk of graft-versus-host disease as well as the relationship with other post-transplant complications, the outcomes of patients with these viremias remain unsatisfactory and even long-term survivors experience increased morbidity.
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Affiliation(s)
- Xin Wang
- Department of Medicine, UMass Memorial Medical Center, Worcester, MA, USA
| | - Shyam A Patel
- Division of Hematology-Oncology, Department of Medicine, UMass Memorial Medical Center, Worcester, MA, USA
| | - Michael Haddadin
- Division of Hematology-Oncology, Department of Medicine, UMass Memorial Medical Center, Worcester, MA, USA
| | - Jan Cerny
- Division of Hematology and Oncology, Department of Medicine, UMass Memorial Medical Center, 55 Lake Avenue North, Worcester, MA, 01655, USA
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50
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Complement inhibition does not impair the clinical antiviral capabilities of virus-specific T-cell therapy. Blood Adv 2021; 4:3252-3257. [PMID: 32697816 DOI: 10.1182/bloodadvances.2020002252] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023] Open
Abstract
Key Points
The use of terminal complement blockade is compatible with virus-specific T-cell (VST) expansion and clinical effectiveness. VST and complement-blocking agent concurrent therapy may be safely used in patients with thrombotic microangiopathy and viral infections.
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