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1
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Crescioli S, Jatiani S, Moise L. With great power, comes great responsibility: the importance of broadly measuring Fc-mediated effector function early in the antibody development process. MAbs 2025; 17:2453515. [PMID: 39819511 PMCID: PMC11810086 DOI: 10.1080/19420862.2025.2453515] [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: 10/23/2024] [Revised: 01/08/2025] [Accepted: 01/09/2025] [Indexed: 01/19/2025] Open
Abstract
The field of antibody therapeutics is rapidly growing, with over 210 antibodies currently approved or in regulatory review and ~ 1,250 antibodies in clinical development. Antibodies are highly versatile molecules that, with strategic design of their antigen-binding domain (Fab) and the domain responsible for mediating effector functions (Fc), can be used in a wide range of therapeutic indications. Building on many years of progress, the biopharmaceutical industry is now advancing innovative research and development by exploring new targets and new formats and using antibody engineering to fine-tune functions tailored to specific disease requirements. In addition to considering the target and the disease context, however, the unique features of each therapeutic antibody trigger a diverse set of Fc-mediated effector functions. To avoid unexpected results on safety and efficacy outcomes during the later stages of the development process, it is crucial to measure the impact of antibody design on Fc-mediated effector function early in the antibody development process. Given the breadth of effector functions antibodies can deploy and the close interplay between the antibody Fab and Fc functional domains, it is important to conduct a comprehensive evaluation of Fc-mediated functions using an array of antigen-specific biophysical and cell-mediated functional assays. Here, we review antibody and Fc receptor properties that influence Fc effector functions and discuss their implications on development of safe and efficacious antibody therapeutics.
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Chok R, Girgulis K, Nickel RS, Guilcher GMT. Systemic Inflammatory Response Post Alemtuzumab and Low-Dose Total Body Irradiation in Pediatric Patients With Sickle Cell Disease: A Case Series. Pediatr Blood Cancer 2025; 72:e31448. [PMID: 39568174 DOI: 10.1002/pbc.31448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 10/31/2024] [Indexed: 11/22/2024]
Affiliation(s)
- Rozalyn Chok
- Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA
| | - Katherine Girgulis
- Section of Oncology/BMT, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Robert S Nickel
- Division of Hematology and Division of Blood and Marrow Transplantation, Children's National Hospital, Washington, District of Columbia, USA
- Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Gregory M T Guilcher
- Section of Oncology/BMT, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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3
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Puthenparampil M, Gaggiola M, Rinaldi F, Nosadini M, Sartori S, Perini P, Gallo P. The immunological bases of alemtuzumab as induction-therapy in pediatric-onset multiple sclerosis. Front Immunol 2025; 15:1509987. [PMID: 39845956 PMCID: PMC11750650 DOI: 10.3389/fimmu.2024.1509987] [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: 10/11/2024] [Accepted: 12/18/2024] [Indexed: 01/24/2025] Open
Abstract
Pediatric-Onset Multiple Sclerosis (POMS) is characterized by both white and grey matter inflammation, as well as by a higher risk of long-term physical and cognitive disability. The peculiar immunopathogenic mechanisms of POMS suggests that the use of induction therapies, including alemtuzumab (ALTZ), might be a promising approach, at least for postpuberal (> 11 yo) POMS. Although no data on the use of induction therapies in POMS are available from clinical trials currently, case series or case reports on the effect of alemtuzumab (ALTZ) have been recently published. In this review we have briefly revised the immunopathogenic features of POMS, as well as on how ALTZ might impact on them, reporting its efficacy observed in different POMS cohorts.
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Affiliation(s)
- Marco Puthenparampil
- Department of Neurosciences, University of Padua, Padua, Italy
- Multiple Sclerosis Centre, Azienda Ospedaliera di Padova, Padua, Italy
- Immune-Mediated Nervous System Disease Study Group, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy
| | - Marta Gaggiola
- Department of Neurosciences, University of Padua, Padua, Italy
- Multiple Sclerosis Centre, Azienda Ospedaliera di Padova, Padua, Italy
| | - Francesca Rinaldi
- Multiple Sclerosis Centre, Azienda Ospedaliera di Padova, Padua, Italy
| | - M. Nosadini
- Immune-Mediated Nervous System Disease Study Group, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy
- Pediatric Neurology and Neurophysiology Unit, Department of Women’s and Children’s Health, University Hospital of Padova, Padua, Italy
| | - S. Sartori
- Immune-Mediated Nervous System Disease Study Group, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy
- Pediatric Neurology and Neurophysiology Unit, Department of Women’s and Children’s Health, University Hospital of Padova, Padua, Italy
| | - Paola Perini
- Multiple Sclerosis Centre, Azienda Ospedaliera di Padova, Padua, Italy
| | - Paolo Gallo
- Department of Neurosciences, University of Padua, Padua, Italy
- Multiple Sclerosis Centre, Azienda Ospedaliera di Padova, Padua, Italy
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4
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Druey KM, Arnaud L, Parikh SM. Systemic capillary leak syndrome. Nat Rev Dis Primers 2024; 10:86. [PMID: 39543164 DOI: 10.1038/s41572-024-00571-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/09/2024] [Indexed: 11/17/2024]
Abstract
The vascular endothelial barrier maintains intravascular volume and metabolic homeostasis. Although plasma fluids and proteins extravasate continuously from tissue microvasculature (capillaries, post-capillary venules), systemic vascular leakage increases in critical illness associated with sepsis, burns and trauma, among others, or in association with certain drugs or toxin exposures. Systemically dysregulated fluid homeostasis, which can lead to hypovolaemia, hypotensive shock and widespread tissue oedema, has been termed systemic capillary leak syndrome (SCLS) when overt secondary causes (for example, heart or liver failure) are excluded. In severe forms, SCLS is complicated by compartment syndrome in the extremities and multi-organ dysfunction syndrome due to shock and systemic hypoperfusion. The different forms of SCLS include idiopathic SCLS (ISCLS) and secondary SCLS (SSCLS), which can be triggered by several conditions, including certain infections and haematological malignancies. A subgroup of patients with ISCLS have monoclonal gammopathy-associated SCLS (also known as Clarkson disease), which is an ultra-rare and extreme form of ISCLS. ISCLS can be managed effectively with monthly prophylactic immunoglobulin therapy whereas SSCLS frequently does not recur once the underlying condition resolves or the offending agent is discontinued. Thus, differentiation between ISCLS, SSCLS and other causes of oedema is crucial for quick diagnosis and positive patient outcomes.
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Affiliation(s)
- Kirk M Druey
- Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
| | - Laurent Arnaud
- Department of Rheumatology, French National Reference Center for Autoimmune Diseases (RESO), INSERM UMR-S 1109, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Samir M Parikh
- Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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5
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Mahomed S. Broadly neutralizing antibodies for HIV prevention: a comprehensive review and future perspectives. Clin Microbiol Rev 2024; 37:e0015222. [PMID: 38687039 PMCID: PMC11324036 DOI: 10.1128/cmr.00152-22] [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] [Indexed: 05/02/2024] Open
Abstract
SUMMARYThe human immunodeficiency virus (HIV) epidemic remains a formidable global health concern, with 39 million people living with the virus and 1.3 million new infections reported in 2022. Despite anti-retroviral therapy's effectiveness in pre-exposure prophylaxis, its global adoption is limited. Broadly neutralizing antibodies (bNAbs) offer an alternative strategy for HIV prevention through passive immunization. Historically, passive immunization has been efficacious in the treatment of various diseases ranging from oncology to infectious diseases. Early clinical trials suggest bNAbs are safe, tolerable, and capable of reducing HIV RNA levels. Although challenges such as bNAb resistance have been noted in phase I trials, ongoing research aims to assess the additive or synergistic benefits of combining multiple bNAbs. Researchers are exploring bispecific and trispecific antibodies, and fragment crystallizable region modifications to augment antibody efficacy and half-life. Moreover, the potential of other antibody isotypes like IgG3 and IgA is under investigation. While promising, the application of bNAbs faces economic and logistical barriers. High manufacturing costs, particularly in resource-limited settings, and logistical challenges like cold-chain requirements pose obstacles. Preliminary studies suggest cost-effectiveness, although this is contingent on various factors like efficacy and distribution. Technological advancements and strategic partnerships may mitigate some challenges, but issues like molecular aggregation remain. The World Health Organization has provided preferred product characteristics for bNAbs, focusing on optimizing their efficacy, safety, and accessibility. The integration of bNAbs in HIV prophylaxis necessitates a multi-faceted approach, considering economic, logistical, and scientific variables. This review comprehensively covers the historical context, current advancements, and future avenues of bNAbs in HIV prevention.
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Affiliation(s)
- Sharana Mahomed
- Centre for the AIDS
Programme of Research in South Africa (CAPRISA), Doris Duke Medical
Research Institute, Nelson R Mandela School of Medicine, University of
KwaZulu-Natal, Durban,
South Africa
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6
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Sobia P, Mahomed S, Sivro A, Paul S, Osman F, Harkoo I, Garrett N, Karim QA, Karim SSA, Archary D. Circulating immunoglobulins and transient lymphocytopenia in a sub-study of CAPRISA 012B, testing HIV monoclonal antibodies in a phase 1 trial. Sci Rep 2024; 14:13499. [PMID: 38866888 PMCID: PMC11169379 DOI: 10.1038/s41598-024-63902-2] [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: 07/10/2023] [Accepted: 06/03/2024] [Indexed: 06/14/2024] Open
Abstract
Acute, transient lymphocytopenia, not clinically significant was observed in the CAPRISA 012B phase 1 clinical trial following administration of broadly neutralizing antibodies (bnAb)-CAP256V2LS alone or with VRC07-523LS. Lymphocytopenia was assigned upon a > 50% decline in absolute lymphocyte counts following bnAb administration. We posited that systemic immunoglobulins (Igs), and cytokine profiles of eight women who developed lymphocytopenia were different to the 12 women without lymphocytopenia. Plasma Ig subclasses (IgG)/isotypes (IgM/IgA), and 27 cytokines were measured at enrolment (prior to bnAbs) and at days 1, 7, 28, 56 post-bnAb administration. IgG subclasses, IgM and total lymphocyte counts were significantly lower prior to bnAbs in women with gradable lymphocytopenia than those without. Gradable lymphocytopenia compared to non-lymphocytopenia women had significantly higher MIP-1β from enrolment up to day 56. TNF-α was significantly lower in gradable lymphocytopenia compared to non-lymphocytopenia women for enrolment, days 7, 28 and 56 except for day 1. Within the gradable and within the non-lymphocytopenia women, from enrolment to day 1, significantly elevated IL-6, IL-8, IP-10, MCP-1, G-CSF and IL-1RA were found. Additionally, within the gradable lymphocytopenia women, 9 additional cytokines (TNF-α, MIP-1α, MIP-1β, RANTES, Basic FGF, eotaxin, IFN-γ, IL-17A and IL-4) were significantly elevated at day 1 post-bnAbs compared to enrolment. This sub study presents preliminary findings to support the monitoring of baseline immunological markers including lymphocyte counts for assessing the development of transient lymphocytopenia. In high-risk settings conducting clinical trials testing bnAbs for HIV prevention, understanding factors that could amplify rates of lymphocytopenia, even if transient, remain undefined.
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Affiliation(s)
- Parveen Sobia
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 2nd Floor, Doris Duke Medical Research Institute, 719 Umbilo Road, Durban, 4041, South Africa
| | - Sharana Mahomed
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 2nd Floor, Doris Duke Medical Research Institute, 719 Umbilo Road, Durban, 4041, South Africa
- Department of Medical Microbiology, University of Kwazulu-Natal, Durban, South Africa
| | - Aida Sivro
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 2nd Floor, Doris Duke Medical Research Institute, 719 Umbilo Road, Durban, 4041, South Africa
- Department of Medical Microbiology, University of Kwazulu-Natal, Durban, South Africa
- JC Wilt Infectious Disease Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
| | - Stephane Paul
- GIMAP (EA3064), University of Saint-Etienne/University of Lyon, Saint-Étienne, France
| | - Farzana Osman
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 2nd Floor, Doris Duke Medical Research Institute, 719 Umbilo Road, Durban, 4041, South Africa
| | - Ishana Harkoo
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 2nd Floor, Doris Duke Medical Research Institute, 719 Umbilo Road, Durban, 4041, South Africa
| | - Nigel Garrett
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 2nd Floor, Doris Duke Medical Research Institute, 719 Umbilo Road, Durban, 4041, South Africa
| | - Quarraisha Abdool Karim
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 2nd Floor, Doris Duke Medical Research Institute, 719 Umbilo Road, Durban, 4041, South Africa
- Department of Epidemiology, Columbia University, New York, NY, USA
| | - Salim S Abdool Karim
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 2nd Floor, Doris Duke Medical Research Institute, 719 Umbilo Road, Durban, 4041, South Africa
- Department of Epidemiology, Columbia University, New York, NY, USA
| | - Derseree Archary
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 2nd Floor, Doris Duke Medical Research Institute, 719 Umbilo Road, Durban, 4041, South Africa.
- Department of Medical Microbiology, University of Kwazulu-Natal, Durban, South Africa.
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De Togni E, Cole O, Abboud R. Janus kinase inhibition in the treatment and prevention of graft-versus-host disease. Front Immunol 2024; 15:1304065. [PMID: 38380328 PMCID: PMC10877010 DOI: 10.3389/fimmu.2024.1304065] [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: 09/28/2023] [Accepted: 01/18/2024] [Indexed: 02/22/2024] Open
Abstract
Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). For many years, corticosteroids have been the mainstay treatment for GVHD, but cases of steroid-refractory GVHD and the severe adverse effects of high-dose corticosteroids have increased the need for preventative and therapeutic strategies for GVHD. Due to the nature of alloreactive T cells, GVHD is inherently linked to the graft-versus-leukemia (GVL) effect, the therapeutic driving force behind stem cell transplantation. A considerable clinical challenge is to preserve GVL while suppressing GVHD. The field of GVHD research has greatly expanded over the past decades, including advancements in T cell modulation and depletion, antibody therapies, chemotherapeutics, cellular therapies, and Janus kinase inhibition. In this review, we discuss current approaches and advances in the prophylaxis and treatment of GVHD with a focus on new emerging advancements in Janus kinase inhibitor therapy.
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Affiliation(s)
- Elisa De Togni
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| | - Oladipo Cole
- Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States
| | - Ramzi Abboud
- Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States
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8
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Zhang Y, Wen X, OuYang Y, Hu Y, Fang X, Zhang J, Yuan Y. Severe cytokine release syndrome induced by immune checkpoint inhibitors in cancer patients - A case report and review of the literature. Heliyon 2024; 10:e24380. [PMID: 38293388 PMCID: PMC10826737 DOI: 10.1016/j.heliyon.2024.e24380] [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: 11/20/2023] [Revised: 12/20/2023] [Accepted: 01/08/2024] [Indexed: 02/01/2024] Open
Abstract
Cytokine release syndrome (CRS) can be induced by immune checkpoint inhibitors (ICIs). Although the incidence of CRS is low, it is often underreported. Here, we report two severe CRS cases and summarize and review 51 patients with ICI-induced CRS to explore the possible contributing factors to the disease prognosis and provide assistance for therapy. Our analysis found that the population with ICI-induced CRS consists mainly of male patients with an average age of 61.74 years. The primary malignant tumor type was lung cancer, and the clinical stage of most patients was stage IV. Notably, patients who experience a longer time to CRS onset, higher IL-6 levels, and lower platelet counts may be more likely to develop severe CRS. Cardiovascular, respiratory, neurological, and coagulation toxicities are more common in higher-grade CRS and may serve as markers for patient experiencing ICU admission, oxygen supplementation, hypotension, high-dose vasopressors usage, and intubation.
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Affiliation(s)
- Yujing Zhang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
| | - Xiaoyue Wen
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
| | - Yaqi OuYang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
| | - Yingying Hu
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
| | - Xiangzhi Fang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
| | - Jiancheng Zhang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
| | - Yin Yuan
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
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9
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Matarasso S, Assouline S. Mosunetuzumab and the emerging role of T-cell-engaging therapy in follicular lymphoma. Future Oncol 2023; 19:2083-2101. [PMID: 37882361 DOI: 10.2217/fon-2023-0274] [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: 10/27/2023] Open
Abstract
Follicular lymphoma (FL) is the most common indolent lymphoma. Since the advent of rituximab, FL has seen a progressive improvement in patient prognosis. While chemotherapy combined with an anti-CD20 monoclonal antibody remains standard first-line therapy, most patients will relapse and require subsequent therapy. T-cell-redirecting therapies can be very potent and are transforming the therapeutic landscape in the relapsed and refractory (R/R) setting. T-cell-dependent bispecific antibodies, of which mosunetuzumab is the first to be approved for R/R FL, are proving to be a highly effective, 'off-the-shelf' option with manageable toxicities. This review covers approved treatments for R/R FL and focuses on preclinical and clinical data available for mosunetuzumab (Lunsumio™), with the goal of determining its role in the treatment of R/R FL.
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Affiliation(s)
- Sarah Matarasso
- Lady Davis Institute, Jewish General Hospital, McGill University, 3755 Cote Ste Catherine, E725, Montreal, QC, H3T 1E2, Canada
| | - Sarit Assouline
- Lady Davis Institute, Jewish General Hospital, McGill University, 3755 Cote Ste Catherine, E725, Montreal, QC, H3T 1E2, Canada
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10
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Moore JE, Bloom PC, Chu CC, Bruno JE, Herne CA, Baran AM, Quataert SA, Mosmann TR, Taylor RP, Wallace DS, Elliott MR, Barr PM, Zent CS. Rituximab induced cytokine release with high serum IP-10 (CXCL10) concentrations is associated with infusion reactions. Leuk Res 2023; 129:107072. [PMID: 37003030 PMCID: PMC10219853 DOI: 10.1016/j.leukres.2023.107072] [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: 02/17/2023] [Revised: 03/18/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
Monoclonal antibody induced infusion reactions (IRs) can be serious and even fatal. We used clinical data and blood samples from 37 treatment naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) initiating therapy for progressive disease with a single 50 mg dose of intravenous (IV) rituximab at 25 mg/h. Twenty-four (65 %) patients had IRs at a median of 78 min (range 35-128) and rituximab dose of 32 mg (range 15-50). IR risk did not correlate with patient or CLL characteristics, CLL counts or CD20 levels, or serum rituximab or complement concentrations. Thirty-five (95 %) patients had cytokine release response with a ≥ 4-fold increase in serum concentration of ≥ 1 inflammatory cytokine. IRs were associated with significantly higher post-infusion serum concentrations of gamma interferon induced cytokines IP-10, IL-6 and IL-8. IP-10 concentrations increased ≥ 4-fold in all patients with an IR and were above the upper limit of detection (40,000 pg/ml) in 17 (71 %). In contrast, to only three (23 %) patients without an IR had an ≥ 4-fold increase in serum concentrations of IP-10 (highest 22,013 pg/ml). Our data suggest that cytokine release could be initiated by activation of effector cells responsible for clearance of circulating CLL cells with IRs occurring in those with higher levels of gamma interferon induced cytokines. These novel insights could inform future research to better understand and manage IRs and understand the role of cytokines in the control of cytotoxic immune responses to mAb.
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Affiliation(s)
- Jeremiah E Moore
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States; Department of Pharmacy, University of Rochester Medical Center, Rochester, NY, United States
| | - Paige C Bloom
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States
| | - Charles C Chu
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States; Division of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, United States
| | - Jennifer E Bruno
- Center for Vaccine Biology & Immunology, University of Rochester Medical Center, Rochester, NY, United States; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States
| | - Christine A Herne
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States
| | - Andrea M Baran
- Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, United States
| | - Sally A Quataert
- Center for Vaccine Biology & Immunology, University of Rochester Medical Center, Rochester, NY, United States; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States
| | - Timothy R Mosmann
- Center for Vaccine Biology & Immunology, University of Rochester Medical Center, Rochester, NY, United States; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States
| | - Ronald P Taylor
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, United States
| | - Danielle S Wallace
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States; Division of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, United States
| | - Michael R Elliott
- Center for Cell Clearance and the Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, United States
| | - Paul M Barr
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States; Division of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, United States
| | - Clive S Zent
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States; Division of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, United States.
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11
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Chen X, Li P, Tian B, Kang X. Serious adverse events and coping strategies of CAR-T cells in the treatment of malignant tumors. Front Immunol 2022; 13:1079181. [PMID: 36569917 PMCID: PMC9772271 DOI: 10.3389/fimmu.2022.1079181] [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: 10/25/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022] Open
Abstract
Chimeric antigen receptor T (CAR-T) cells technology has been successfully used in the treatment of B cell-derived hematological tumors and multiple myeloma. CAR-T cells are also being studied in a variety of solid tumors. Current clinical reports on CAR-T cells in the treatment of malignant tumors are abundant. The tumor-killing activity of CAR-T cells and the unique adverse effects of CAR-T cells have been confirmed by many studies. There is evidence that serious adverse events can be life-threatening. CAR-T cells therapy is increasingly used in clinical settings, so it is important to pay attention to its serious adverse events. In this review, we summarized the serious adverse events of CAR-T cells in the treatment of malignant tumors by reading literature and searching relevant clinical studies, and discussed the management and treatment of serious adverse events in an effort to provide theoretical support for clinicians who deal with such patients.
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12
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An albumin-angiotensin converting enzyme 2-based SARS-CoV-2 decoy with FcRn-driven half-life extension. Acta Biomater 2022; 153:411-418. [PMID: 36162760 PMCID: PMC9508356 DOI: 10.1016/j.actbio.2022.09.048] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/23/2022] [Accepted: 09/19/2022] [Indexed: 12/05/2022]
Abstract
The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants and breakthrough infections despite available coronavirus disease 2019 (COVID-19) vaccines calls for antiviral therapeutics. The application of soluble angiotensin converting enzyme 2 (ACE2) as a SARS-CoV-2 decoy that reduces cell bound ACE2-mediated virus entry is limited by a short plasma half-life. This work presents a recombinant human albumin ACE2 genetic fusion (rHA-ACE2) to increase the plasma half-life by an FcRn-driven cellular recycling mechanism, investigated using a wild type (WT) albumin sequence and sequence engineered with null FcRn binding (NB). Binding of rHA-ACE2 fusions to SARS-CoV-2 spike protein subdomain 1 (S1) was demonstrated (WT-ACE2 KD = 32.8 nM and NB-ACE2 KD = 31.7 nM) using Bio-Layer Interferometry and dose-dependent in vitro inhibition of host cell infection of pseudotyped viruses displaying surface SARS-CoV-2 spike (S) protein. FcRn-mediated in vitro recycling was translated to a five times greater plasma half-life of WT-ACE2 (t½ β = 13.5 h) than soluble ACE2 (t½ β = 2.8 h) in humanised FcRn/albumin double transgenic mice. The rHA-ACE2-based SARS-CoV-2 decoy system exhibiting FcRn-driven circulatory half-life extension introduced in this work offers the potential to expand and improve the anti-COVID-19 anti-viral drug armoury. Statement of significance The COVID-19 pandemic has highlighted the need for rapid development of efficient antiviral therapeutics to combat SARS-CoV-2 and new mutants to lower morbidity and mortality in severe cases, and for people that are unable to receive a vaccine. Here we report a therapeutic albumin ACE2 fusion protein (rHA-ACE2), that can bind SARS-CoV-2 S protein decorated virus-like particles to inhibit viral infection, and exhibits extended in vivo half-life compared to ACE2 alone. Employing ACE2 as a binding decoy for the virus is expected to efficiently inhibit all SARS-CoV-2 mutants as they all rely on binding with endogenous ACE2 for viral cell entry and, therefore, rHA-ACE2 constitutes a versatile addition to the therapeutic arsenal for combatting COVID-19.
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DALGIÇ CT, GÖKMEN ENM, ÖZIŞIK M, BAKLAN MA, YÜCEYAR N. Successful Rapid Drug Desensitization with A Modified Protocol To Alemtuzumab in A Multiple Sclerosis Patient with Severe Immediate-Type Hypersensitivity Reaction. Noro Psikiyatr Ars 2022; 59:237-241. [PMID: 36160076 PMCID: PMC9466639 DOI: 10.29399/npa.27371] [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: 08/07/2020] [Accepted: 06/24/2021] [Indexed: 06/16/2023] Open
Abstract
Alemtuzumab is a humanized monoclonal antibody targeting the CD52 antigen on lymphocyte surfaces. The intravenous administration of alemtuzumab provokes the depletion of lymphocytes by antibody-dependent and complement-mediated cellular cytotoxicity. Resulting cytotoxicity leads to 'first-dose infusion-related reactions in more than 90% of the patients, fewer than 3% being severe cases. We present the first successful modified rapid drug desensitization (RDD) protocol to alemtuzumab in an active relapsing-remitting multiple sclerosis (RRMS) patient. The forty-year-old female patient had an immunologically-mediated mixed-type (co-occurring IgE-mediated and cytokine release syndromes) hypersensitivity reaction (HSR) verified with a drug skin test. As the patient had severe HSR and there was no other option to treat RRMS at that time; two courses of 12 mg alemtuzumab with one-year intervals were administrated successfully using the modified 12-step intravenous RDD protocol. By experience, RDD is known as a safe and effective therapy option allowing alemtuzumab treatment targeted for the aforementioned type of MS.
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Affiliation(s)
- Ceyda Tunakan DALGIÇ
- Division of Allergy and Immunology, Department of Internal Medicine, Faculty of Medicine, Ege University, İzmir, Turkey
| | - Emine Nihal mete GÖKMEN
- Division of Allergy and Immunology, Department of Internal Medicine, Faculty of Medicine, Ege University, İzmir, Turkey
| | - Melih ÖZIŞIK
- Division of Allergy and Immunology, Department of Internal Medicine, Faculty of Medicine, Ege University, İzmir, Turkey
| | | | - Nur YÜCEYAR
- Department of Neurology, Faculty of Medicine, Ege University, İzmir, Turkey
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14
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Leckey R, Borsellino L, Rawlings AM, Ashkenas J, Suri A. Acute infusion effects in relapsing multiple sclerosis patients receiving alemtuzumab under a modified prophylaxis regimen. Mult Scler Relat Disord 2022; 66:104030. [PMID: 35870368 DOI: 10.1016/j.msard.2022.104030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/13/2022] [Accepted: 07/03/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Use of alemtuzumab in relapsing multiple sclerosis (RMS) is limited by safety concerns, notably risk of rare, serious vascular events. Along with other vital sign (VS) changes, acute increase in systolic blood pressure (SBP) is monitored as a marker of vascular risk. Peri-infusion prophylaxis is used to manage clinical risk by moderating cytokine release; protocols are not fully specified and vary across sites. Here, we report a modified prophylaxis regimen developed at Maritime Neurology. This single-center observational cohort study (NCT04633967) aimed to examine acute responses (VS events and infusion-associated reactions) in RMS patients receiving alemtuzumab infusion under this regimen. In a post hoc analysis, we examined incidence of acute SBP increase at this clinic versus the Bayshore network of Canadian infusion centers, where a standard prophylaxis regimen is used. METHODS Alemtuzumab was infused on 5 consecutive days (Course 1; n = 29) and 3 consecutive days one year later (Course 2; n = 28). In addition to intravenous methylprednisolone 500mg on each infusion day, patients received daily prophylactic treatment with oral prednisone 50mg from 5 days before to 5 days after treatment (infusion days excepted) and oral H1 and H2 antihistaminics from 7 days before to 7 days after treatment. Excursions in SBP and other VS were relative to prespecified ranges; persistent excursions were those for which two sequential measurements were outside these ranges. In comparing VS events at Maritime Neurology and the Bayshore centers, acute SBP increase was defined as ≥20 mmHg increase in mean SBP, or any SBP reading ≥20% over patient's pre-course baseline. RESULTS Mean (SD) VS were within range at pre-course and all other daily baselines. VS changes, including persistent excursions, were generally subclinical; all infusion-associated reactions were mild. One patient discontinued treatment after Course 1 due to immune thrombocytopenia purpura. Acute SBP increase occurred in 11/28 (39%) Maritime Neurology versus 367/610 (60%) Bayshore (p = 0.028). CONCLUSION The modified peri-infusion prophylaxis regimen was well tolerated and may reduce incidence of acute SBP increase. FUNDING This project was funded by Sanofi, Canada.
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Affiliation(s)
- Richard Leckey
- Maritime Neurology, 349 Herring Cove Road, Herring Cove, Halifax, NS B3R 1V9, Canada; Division of Neurology, Dalhousie University, Halifax, NS, Canada.
| | | | | | | | - Amit Suri
- Sanofi Canada, Mississauga, ON, Canada
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15
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Madsen NH, Gad M, Larsen J. Development of a flow cytometry-based potency assay for prediction of cytokine storms induced by biosimilar monoclonal antibodies. J Immunol Methods 2022; 502:113231. [PMID: 35122772 DOI: 10.1016/j.jim.2022.113231] [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: 09/17/2021] [Revised: 01/02/2022] [Accepted: 01/28/2022] [Indexed: 11/19/2022]
Abstract
Cytokine release syndrome (CRS) is an undesired immune reaction that may cause dangerous side effects after the administration of novel biological therapies. In vitro cytokine release assays (CRA) are used for preclinical safety assessment prior to first-in-man dose administration of therapeutic monoclonal antibodies (mAbs). A variety of CRA platforms has been developed where the analysis of secreted cytokines is performed. Analysis of T cell activation markers is not performed routinely in CRA platforms and few studies have described intracellular cytokine levels after stimulation with therapeutic mAbs. In the present study, we performed a CRA using intracellular cytokine staining and assessment of extracellular T cell activation markers by flow cytometry. We used commercially available reference mAbs for the stimulation of peripheral blood mononuclear cells (PBMCs). We found that stimulation using solid phase (SP) dry coating with two different CD28 antibodies and muromonab-CD3 increased the percentage of IFN-ɣ + CD4+ and CD8+ T cells as well as of CD3-CD56+ NK cells compared to stimulation with antibodies in aqueous phase (AP). Expression of the T cell activation markers CD25 and CD69 on CD4+ and CD8+ T cells was also increased upon SP muromonab-CD3 stimulation. Using multiplex cytokine assessment, we showed that stimulation in AP using ANC28.1, CD28.2 and muromonab-CD3 led to an increase of IFN-ɣ, GM-CSF, TNF-α, and IL-2 secretion. Stimulation of PBMCs preincubated at high-density culture led to an increase in IFN-ɣ production but not in the expression of activation markers compared to low-density culture. Our findings demonstrated that flow cytometry analyses for assessing relevant T cell and NK cell markers may be used as a supplement to multiplex cytokine analysis in CRAs. The approach may be a valuable addition that enables a more precise description of the mechanisms leading to CRS.
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Affiliation(s)
| | - Monika Gad
- Bioneer A/S, Kogle Allé 2, DK-2970 Hørsholm, Denmark
| | - Jesper Larsen
- Bioneer A/S, Kogle Allé 2, DK-2970 Hørsholm, Denmark.
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16
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Anticancer Drugs-induced Capillary Leak Syndrome. Kidney Int Rep 2022; 7:945-953. [PMID: 35570987 PMCID: PMC9091576 DOI: 10.1016/j.ekir.2022.02.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 01/02/2023] Open
Abstract
The term capillary leak syndrome (CLS) describes the manifestations associated with an increased capillary permeability to proteins leading to an escape of plasma from the blood circulatory system to surrounding tissues, muscle, organs, or body cavities. This results clinically in the typical triad of hypotension, edema, and elevated hematocrit. The more severe cases of CLS may present with cardiovascular collapse, shock, and death. The most classic form of this pathology is represented by the idiopathic systemic CLS (SCLS) also called Clarkson’s disease, but capillary leaks are also described as adverse drug reactions foremost among which are anticancer drugs. This review will focus on oncologic drugs such as gemcitabine, therapeutic growth factors or cytokines, and monoclonal antibodies (mAbs) that appear now as the strongest candidates for anticancer drug-induced CLS.
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17
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A mosquito AgTRIO monoclonal antibody reduces early Plasmodium infection of mice. Infect Immun 2021; 90:e0035921. [PMID: 34724388 DOI: 10.1128/iai.00359-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Malaria begins when an infected mosquito injects saliva containing Plasmodium sporozoites into the skin of a vertebrate host. Passive immunization of mice with mosquito AgTRIO antisera offers significant protection against Plasmodium infection of mice. Furthermore, passive transfer of both AgTRIO antisera and an anti-circumsporozoite protein monoclonal antibody provides synergistic protection. In this study, we generated monoclonal antibodies against AgTRIO to delineate the regions of AgTRIO associated with protective immunity. Monoclonal antibody 13F-1 markedly reduced Plasmodium infection in mice and recognized a region, VDDLMAKFN, in the carboxyl terminus of AgTRIO. 13F-1 is an IgG2a isotype monoclonal antibody and the Fc region is required for protection. These data will aid in the generation of future malaria vaccines that may include both pathogen and vector antigens.
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18
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Ito S, Miwa K, Hattori C, Aida T, Tsuchiya Y, Mori K. Highly sensitive in vitro cytokine release assay incorporating high-density preculture. J Immunotoxicol 2021; 18:136-143. [PMID: 34644231 DOI: 10.1080/1547691x.2021.1984617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Immunostimulatory effects of monoclonal antibodies (mAb) through binding to Fcγ receptors (FcγR) on immune cells are a likely cause of cytokine release syndrome. However, it is difficult to detect the potential risk of FcγR-dependent cytokine release associated with mAb in the current standard cytokine release assays (CRA), including the air-drying solid-phase method using human peripheral blood mononuclear cells (PBMC). To increase the sensitivity to detect FcγR-dependent cytokine release due to mAb, a high-density preculture (HDC) method was incorporated into the air-drying solid-phase CRA. Here, PBMC were exposed to panitumumab, trastuzumab, rituximab, or alemtuzumab at 0.1, 0.3, 1, and 3 μg/well for 24 or 48 hr under both non-HDC and HDC conditions. T-cell agonists (anti-CD3 mAb, anti-CD28 super-agonist [SA] mAb) were used as reference mAb. Panitumumab, trastuzumab, rituximab, or alemtuzumab induced cytokine release under both non-HDC and HDC conditions, and cytokine release caused by alemtuzumab was more pronounced under HDC conditions. To investigate FcγR involvement in cytokine release associated with panitumumab, trastuzumab, rituximab, and alemtuzumab, CRA of these four mAb were conducted with anti-FcγRI, -FcγRII, or -FcγRIII F(ab')2 fragments. The results showed cytokine release caused by trastuzumab, rituximab, and alemtuzumab was significantly suppressed by anti-FcγRIII F(ab')2 pretreatment, and slightly reduced by anti-FcγRI or anti-FcγRII pretreatment, indicating these mAb induced FcγR (especially FcγRIII)-dependent cytokine release from PBMC. Cytokine release caused by panitumumab was slightly suppressed by anti-FcγRIII F(ab')2 pretreatment. Anti-CD3 mAb and anti-CD28 SA mAb also induced significant release of cytokines under HDC conditions compared with that under non-HDC conditions. In conclusion, CRA incorporating HDC into the air-drying solid-phase method using human PBMC could sensitively capture the FcγR-dependent cytokine release potential of mAb.
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Affiliation(s)
- Shiho Ito
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, Edogawa-ku, Tokyo, Japan
| | - Kyoko Miwa
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, Edogawa-ku, Tokyo, Japan
| | - Chiharu Hattori
- Oncology Research Laboratories I, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan
| | - Tetsuo Aida
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, Edogawa-ku, Tokyo, Japan
| | - Yoshimi Tsuchiya
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, Edogawa-ku, Tokyo, Japan
| | - Kazuhiko Mori
- Transrational Research, Daiichi Sankyo RD Novare Co, Ltd, Edogawa-ku, Tokyo, Japan
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19
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Fabrizio VA, Curran KJ. Clinical experience of CAR T cells for B cell acute lymphoblastic leukemia. Best Pract Res Clin Haematol 2021; 34:101305. [PMID: 34625231 DOI: 10.1016/j.beha.2021.101305] [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: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 10/20/2022]
Abstract
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment for both pediatric and adult patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). Clinical trial results across multiple institutions with different CAR constructs report significant response rates in treated patients. One product (tisagenlecleucel) is currently FDA approved for the treatment of R/R B-ALL in patients <26 y/o. Successful application of this therapy is limited by high relapse rates, potential for significant toxicity, and logistical issues surrounding collection/production. Herein, we review published data on the use of CAR T cells for B-ALL, including results from early pivotal clinical trials, relapse data, incidence of toxicity, and mechanisms to optimize CAR T cell therapy.
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Affiliation(s)
- Vanessa A Fabrizio
- Duke University, Department of Pediatrics, Division of Pediatric Transplant and Cellular Therapy, 2400 Pratt Road, Durham, NC, 27705, USA.
| | - Kevin J Curran
- Memorial Sloan Kettering Cancer Center, Department of Pediatrics, 1275 York Avenue, New York, NY, 10065, USA; Weill Cornell Medical College, Department of Pediatrics, 1275 York Avenue, New York, NY, 10065, USA.
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20
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Mansouri V, Yazdanpanah N, Rezaei N. The immunologic aspects of cytokine release syndrome and graft versus host disease following CAR T cell therapy. Int Rev Immunol 2021; 41:649-668. [PMID: 34607523 DOI: 10.1080/08830185.2021.1984449] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Chimeric antigen receptor (CAR) T cells are the pioneers of cancer immunotherapy, which to this date have several FDA-approved products. They have been substantially improved since their first introduction in 1993 and have shown promising results regardless of their inevitable side effects. Cytokine release syndrome (CRS), the most common toxicity after CAR T cell treatment, is affiliated to a systemic inflammation through surge of cytokines, mainly IL-6, IL-1, and INF-γ. Furthermore, difference between histocompatibility antigens activates the graft versus host disease (GvHD) effect of the allogenic CAR T cells against the host cells. Immunological reactions induced by CAR T cells in the form of CRS or GvHD is necessary for fostering good responses, while excess reactions can potentially threaten patient life. In this review, we first describe the history, applications, and structure of CAR T cells, followed by a comprehensive review of CRS regarding its definition, management, and immunological aspects. Finally, we discuss about the clinical aspects of CRS and GvHD after CAR T cell therapy and how to harness anti-tumoral effects, while mitigating the adverse effects.
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Affiliation(s)
- Vahid Mansouri
- Gene Therapy Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Niloufar Yazdanpanah
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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21
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Pfeuffer S, Ruck T, Pul R, Rolfes L, Korsukewitz C, Pawlitzki M, Wildemann B, Klotz L, Kleinschnitz C, Scalfari A, Wiendl H, Meuth SG. Impact of previous disease-modifying treatment on effectiveness and safety outcomes, among patients with multiple sclerosis treated with alemtuzumab. J Neurol Neurosurg Psychiatry 2021; 92:1007-1013. [PMID: 33712515 PMCID: PMC8372391 DOI: 10.1136/jnnp-2020-325304] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 01/14/2021] [Accepted: 02/07/2021] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Alemtuzumab is effective in patients with active multiple sclerosis but has a complex safety profile, including the development of secondary autoimmunity. Most of patients enrolled in randomised clinical trials with alemtuzumab were either treatment naïve or pretreated with injectable substances. Other previous disease-modifying treatments (DMTs) were not used in the study cohorts, and therefore, associated risks might yet remain unidentified. METHODS We retrospectively evaluated a prospective dual-centre alemtuzumab cohort of 170 patients. We examined the baseline characteristics as well as safety and effectiveness outcomes, including the time to first relapse, the time to 3 months confirmed disability worsening and the time to secondary autoimmunity. RESULTS The regression analysis showed that, among all previously used DMTs, the pretreatment with fingolimod (n=33 HRs for the time to first relapse (HR 5.420, 95% CI 2.520 to 11.660; p<0.001)) and for the time to worsening of disability (HR 7.676, 95% CI 2.870 to 20.534; p<0.001). Additionally, patients pretreated with fingolimod were more likely to experience spinal relapses (55% vs 10% among previously naïve patients; p<0.001) and had an increased risk of secondary autoimmunity (HR 5.875, 95% CI 2.126 to 16.27; p<0.001). CONCLUSION In the real-world setting, we demonstrated suboptimal disease control and increased risk of secondary autoimmunity following alemtuzumab, among patients previously treated with fingolimod. These data can provide guidance for improving MS therapeutic management.
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Affiliation(s)
- Steffen Pfeuffer
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Tobias Ruck
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.,Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany
| | - Refik Pul
- Department of Neurology, Universitat Duisburg-Essen, Duisburg, Germany
| | - Leoni Rolfes
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Catharina Korsukewitz
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Marc Pawlitzki
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Brigitte Wildemann
- Division of Molecular Neuroimmunology, Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany
| | - Luisa Klotz
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | | | - Antonio Scalfari
- Centre for Neuroscience, Division of Experimental Medicine, Hammersmith Hospital, Imperial College London, London, UK
| | - Heinz Wiendl
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Sven G Meuth
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.,Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany
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22
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Cosenza M, Sacchi S, Pozzi S. Cytokine Release Syndrome Associated with T-Cell-Based Therapies for Hematological Malignancies: Pathophysiology, Clinical Presentation, and Treatment. Int J Mol Sci 2021; 22:ijms22147652. [PMID: 34299273 PMCID: PMC8305850 DOI: 10.3390/ijms22147652] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 07/15/2021] [Accepted: 07/15/2021] [Indexed: 01/08/2023] Open
Abstract
Cytokines are a broad group of small regulatory proteins with many biological functions involved in regulating the hematopoietic and immune systems. However, in pathological conditions, hyperactivation of the cytokine network constitutes the fundamental event in cytokine release syndrome (CRS). During the last few decades, the development of therapeutic monoclonal antibodies and T-cell therapies has rapidly evolved, and CRS can be a serious adverse event related to these treatments. CRS is a set of toxic adverse events that can be observed during infection or following the administration of antibodies for therapeutic purposes and, more recently, during T-cell-engaging therapies. CRS is triggered by on-target effects induced by binding of chimeric antigen receptor (CAR) T cells or bispecific antibody to its antigen and by subsequent activation of bystander immune and non-immune cells. CRS is associated with high circulating concentrations of several pro-inflammatory cytokines, including interleukins, interferons, tumor necrosis factors, colony-stimulating factors, and transforming growth factors. Recently, considerable developments have been achieved with regard to preventing and controlling CRS, but it remains an unmet clinical need. This review comprehensively summarizes the pathophysiology, clinical presentation, and treatment of CRS caused by T-cell-engaging therapies utilized in the treatment of hematological malignancies.
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23
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Abboud R, Wan F, Mariotti J, Arango M, Castagna L, Romee R, Hamadani M, Chhabra S. Cytokine release syndrome after haploidentical hematopoietic cell transplantation: an international multicenter analysis. Bone Marrow Transplant 2021; 56:2763-2770. [PMID: 34262142 DOI: 10.1038/s41409-021-01403-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/14/2021] [Accepted: 06/28/2021] [Indexed: 11/09/2022]
Abstract
Haploidentical related donor transplantation (haplo-HCT) is associated with cytokine release syndrome (CRS). We conducted a multicenter retrospective study to analyze risk factors for CRS and outcomes after haplo-HCT. We included 451 patients from four academic centers receiving both peripheral blood and bone marrow grafts. Severe CRS was more common with PB vs. BM grafts (19.5% vs 4.9%, OR 2.9, p = 0.05). Multivariable analysis identified recipient CMV sero-positivity, prior transplant, HCT-CI score and donor-recipient sex mismatch as risk factors for severe CRS. Outcomes were analyzed with no CRS as the comparison group. Overall survival (OS) was superior with mild CRS (HR 0.64, p = 0.05) and worst with severe CRS (HR 2.12, p = 0.0038). Relapse risk was significantly decreased in both mild CRS (HR 0.38, p < 0.0001) and severe CRS (HR 0.17, p < 0.0001) groups. The risk of non-relapse mortality was notably higher in severe CRS group (HR 8.0, p < 0.0001), but not in mild CRS group. Acute GVHD was similar among groups. Chronic GVHD at 1 year was 18.5% for no CRS, 23% for mild CRS, and 4.3% for severe CRS (p = 0.0023), with the competing risk of early mortality and short follow up of surviving patients contributing to the low chronic GVHD rates in the severe CRS group.
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Affiliation(s)
- Ramzi Abboud
- Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Fei Wan
- Biostatistics Shared Resource Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Jacopo Mariotti
- Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy
| | - Marcos Arango
- Hematology and Stem Cell Transplantation, Hospital Pablo Tobón Uribe, Medellín, Colombia
| | - Luca Castagna
- Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy
| | - Rizwan Romee
- BMT and Cellular Therapy Program, Dana Farber Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Mehdi Hamadani
- BMT and Cellular Therapy Program, Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Saurabh Chhabra
- BMT and Cellular Therapy Program, Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
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24
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Li Q, Deng HB, Liu MJ, Lyu CC, Zhu HB, Wang J, Jiang YL, Pu YD, Jiang YY, Li W, Deng Q. [Analysis of local reactions and efficacy of CD19 chimeric antigen receptor-modified T cells therapy in recurrent/refractory B-cell lymphoma with >7.5 cm lesions]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:570-576. [PMID: 34455744 PMCID: PMC8408490 DOI: 10.3760/cma.j.issn.0253-2727.2021.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
目的 观察病灶>7.5 cm的复发/难治B细胞非霍奇金淋巴瘤（R/R NHL）患者CD19嵌合抗原受体T细胞（CAR-T细胞）治疗的肿瘤局部反应及疗效。 方法 以2018年8月至2020年5月接受CD19 CAR-T细胞治疗的病灶>7.5 cm的32例R/R NHL患者为研究对象，流式细胞仪检测CD19CAR-T细胞的体内扩增情况；酶联免疫吸附测定法检测患者外周血中细胞因子水平；观察全身不良反应及肿瘤局部反应，分析总有效率（ORR）及总生存（OS）情况。 结果 ① 32例患者CAR-T细胞治疗后，13例获得完全缓解（CR）（40.63％），10例获得部分缓解（PR）（31.25％），ORR为71.88％。② 23例有效患者均发生细胞因子释放综合征（CRS），其中1～2级13例，3～4级10例；而疾病稳定+疾病进展（SD+PD）组9例患者CRS均为1～2级（P＝0.030）。③共15例（46.9％）患者发生肿瘤局部反应，其中CR 9例、PR 5例、SD 1例，肿瘤局部反应包括：浅表肿物直径增大且伴红肿热痛；深部肿物表现为腹痛、腹胀、憋气以及肿瘤局部疼痛、烧灼，瘤体增大或伴局部水肿；肿瘤局部出现渗出性病变，可见于腹腔、胸膜腔等。④有效组CD19 CAR-T细胞峰值高于SD+PD组［16.8％（5.3％～48.2％）对2.9％（1.5％～5.7％），z＝−4.297，P<0.001］，有效组中出现肿瘤局部反应患者CD19 CAR-T细胞峰值高于未出现肿瘤局部反应患者［22.2％（10.5％～48.2％）对12.6％（5.3％～21.6％），z＝−3.213，P＝0.001］，多发肿块组CD19 CAR-T细胞峰值高于单发肿块组［35.8％（1.5％～48.2％）对16.8％（10.5％～18.5％），z＝−2.023，P＝0.040］。⑤肿瘤局部反应出现和瘤体缩小时间，均较全身不良反应时间延迟。⑥有效患者中出现肿瘤局部反应者OS率高于未出现肿瘤局部反应者，但差异无统计学意义（75.0％对34.6％，P＝0.169）。 结论 病灶>7.5 cm的R/R NHL患者CD19 CAR-T细胞治疗，近一半出现肿瘤局部反应，发生时间迟于全身不良反应开始的时间。临床试验注册：中国临床试验注册中心（ChiCTR1800018059）
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Affiliation(s)
- Q Li
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - H B Deng
- The First Central Clinical College of Tianjin Medical University, Tianjin 300070, China
| | - M J Liu
- The First Central Clinical College of Tianjin Medical University, Tianjin 300070, China
| | - C C Lyu
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - H B Zhu
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - J Wang
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - Y L Jiang
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - Y D Pu
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - Y Y Jiang
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - W Li
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin 300060, China
| | - Q Deng
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
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Davey AS, Call ME, Call MJ. The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities. Cancers (Basel) 2020; 13:E38. [PMID: 33375550 PMCID: PMC7794933 DOI: 10.3390/cancers13010038] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/20/2020] [Accepted: 12/22/2020] [Indexed: 02/03/2023] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B cell malignancies, improving patient survival and long-term remission. Nonetheless, over 50% of patients experience severe treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity. Differences in severity of toxic side-effects among anti-CD19 CARs suggest that the choice of costimulatory domain makes a significant contribution to toxicity, but comparisons are complicated by additional differences in the hinge and transmembrane (TM) domains of the most commonly used CARs in the clinic, segments that have long been considered to perform purely structural roles. In this perspective, we examine clinical and preclinical data for anti-CD19 CARs with identical antigen-binding (FMC63) and signalling (CD3ζ) domains to unravel the contributions of different hinge-TM and costimulatory domains. Analysis of clinical trials highlights an association of the CD28 hinge-TM with higher incidence of CRS and neurotoxicity than the corresponding sequences from CD8, regardless of whether the CD28 or the 4-1BB costimulatory domain is used. The few preclinical studies that have systematically varied these domains similarly support a strong and independent role for the CD28 hinge-TM sequence in high cytokine production. These observations highlight the value that a comprehensive and systematic interrogation of each of these structural domains could provide toward developing fundamental principles for rational design of safer CAR-T cell therapies.
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Affiliation(s)
- Ashleigh S. Davey
- Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 5052, Australia;
- Department of Medical Biology, The University of Melbourne, Parkville 3052, Australia
| | - Matthew E. Call
- Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 5052, Australia;
- Department of Medical Biology, The University of Melbourne, Parkville 3052, Australia
| | - Melissa J. Call
- Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 5052, Australia;
- Department of Medical Biology, The University of Melbourne, Parkville 3052, Australia
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26
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Stančič B, Qvarfordt B, Berglund MM, Brenden N, Sydow Bäckman M, Fransson M, Nordling S, Magnusson PU. The blood endothelial cell chamber - An innovative system to study immune responses in drug development. Int Immunopharmacol 2020; 90:107237. [PMID: 33310662 DOI: 10.1016/j.intimp.2020.107237] [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: 08/26/2020] [Revised: 11/04/2020] [Accepted: 11/23/2020] [Indexed: 10/22/2022]
Abstract
The risk for adverse immune-mediated reactions, associated with the administration of certain immunotherapeutic agents, should be mitigated early. Infusion reactions to monoclonal antibodies and other biopharmaceuticals, known as cytokine release syndrome, can arise from the release of cytokines via the drug target cell, as well as the recruitment of immune effector cells. While several in vitro cytokine release assays have been proposed up to date, many of them lack important blood components, required for this response to occur. The blood endothelial cell chamber model is an in vitro assay, composed of freshly drawn human whole blood and cultured human primary endothelial cells. Herein, its potential to study the compatibility of immunotherapeutics with the human immune system was studied by evaluating three commercially available monoclonal antibodies and bacterial endotoxin lipopolysaccharide. We demonstrate that the anti-CD28 antibody TGN1412 displayed an adaptive cytokine release profile and a distinct IL-2 response, accompanied with increased CD3+ cell recruitment. Alemtuzumab exhibited a clear cytokine response with a mixed adaptive/innate source (IFNγ, TNFα and IL-6). Its immunosuppressive nature is observed in depleted CD3+ cells. Cetuximab, associated with low infusion reactions, showed a very low or absent stimulatory effect on proinflammatory cytokines. In contrast, bacterial endotoxin demonstrated a clear innate cytokine response, defined by TNFα, IL-6 and IL-1β release, accompanied with a strong recruitment of CD14+CD16+ cells. Therefore, the blood endothelial cell chamber model is presented as a valuable in vitro tool to investigate therapeutic monoclonal antibodies with respect to cytokine release and vascular immune cell recruitment.
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Affiliation(s)
- Brina Stančič
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjöldsväg 20, 751 85, Uppsala University, Uppsala, Sweden; Department of Molecular Biology, Universidad Autónoma de Madrid, and Department of Molecular Neuropathology, Center of Molecular Biology Severo Ochoa (UAM-CSIC), Nicolás Cabrera 1, 28049 Madrid, Spain
| | - Bodil Qvarfordt
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjöldsväg 20, 751 85, Uppsala University, Uppsala, Sweden
| | | | - Nina Brenden
- Swedish Orphan Biovitrum AB, Tomtebodavägen 23A, 112 76 Solna, Sweden
| | | | - Moa Fransson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjöldsväg 20, 751 85, Uppsala University, Uppsala, Sweden
| | - Sofia Nordling
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjöldsväg 20, 751 85, Uppsala University, Uppsala, Sweden
| | - Peetra U Magnusson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjöldsväg 20, 751 85, Uppsala University, Uppsala, Sweden.
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Amigues I, Pearlman AH, Patel A, Reid P, Robinson PC, Sinha R, Kim AH, Youngstein T, Jayatilleke A, Konigon M. Coronavirus disease 2019: investigational therapies in the prevention and treatment of hyperinflammation. Expert Rev Clin Immunol 2020; 16:1185-1204. [PMID: 33146561 PMCID: PMC7879704 DOI: 10.1080/1744666x.2021.1847084] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 11/03/2020] [Indexed: 02/06/2023]
Abstract
Introduction: The mortality of coronavirus disease 2019 (COVID-19) is frequently driven by an injurious immune response characterized by the development of acute respiratory distress syndrome (ARDS), endotheliitis, coagulopathy, and multi-organ failure. This spectrum of hyperinflammation in COVID-19 is commonly referred to as cytokine storm syndrome (CSS). Areas covered: Medline and Google Scholar were searched up until 15th of August 2020 for relevant literature. Evidence supports a role of dysregulated immune responses in the immunopathogenesis of severe COVID-19. CSS associated with SARS-CoV-2 shows similarities to the exuberant cytokine production in some patients with viral infection (e.g.SARS-CoV-1) and may be confused with other syndromes of hyperinflammation like the cytokine release syndrome (CRS) in CAR-T cell therapy. Interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha have emerged as predictors of COVID-19 severity and in-hospital mortality. Expert opinion: Despite similarities, COVID-19-CSS appears to be distinct from HLH, MAS, and CRS, and the application of HLH diagnostic scores and criteria to COVID-19 is not supported by emerging data. While immunosuppressive therapy with glucocorticoids has shown a mortality benefit, cytokine inhibitors may hold promise as 'rescue therapies' in severe COVID-19. Given the arguably limited benefit in advanced disease, strategies to prevent the development of COVID-19-CSS are needed.
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Affiliation(s)
- Isabelle Amigues
- Division of Rheumatology, Department of Medicine, National Jewish Health, Denver, CO, USA
| | - Alexander H Pearlman
- Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Aarat Patel
- Bon Secours Rheumatology Center and Division of Pediatric Rheumatology, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Pankti Reid
- Division of Rheumatology, Department of Internal Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago Medical Center, Chicago, IL, USA
| | - Philip C. Robinson
- School of Clinical Medicine, University of Queensland Faculty of Medicine, Queensland, Australia
| | - Rashmi Sinha
- Department of Medicine, Systemic Juvenile Idiopathic Arthritis Foundation, Cincinnati, OH, USA
| | - Alfred Hj Kim
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
- Andrew M. And Jane M. Bursky Center of Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA
| | - Taryn Youngstein
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Arundathi Jayatilleke
- Division of Rheumatology, Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Maximilian Konigon
- Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Vessillier S, Fort M, O'Donnell L, Hinton H, Nadwodny K, Piccotti J, Rigsby P, Staflin K, Stebbings R, Mekala D, Willingham A, Wolf B. Development of the first reference antibody panel for qualification and validation of cytokine release assay platforms - Report of an international collaborative study. Cytokine X 2020; 2:100042. [PMID: 33458650 DOI: 10.1016/j.cytox.2020.100042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 09/15/2020] [Accepted: 09/16/2020] [Indexed: 10/23/2022] Open
Abstract
Immunomodulatory therapeutics such as monoclonal antibodies (mAb) carry an inherent risk of undesired immune reactions. One such risk is cytokine release syndrome (CRS), a rapid systemic inflammatory response characterized by the secretion of pro-inflammatory cytokines from immune cells. It is crucial for patient safety to correctly identify potential risk of CRS prior to first-in-human dose administration. For this purpose, a variety of in vitro cytokine release assays (CRA) are routinely used as part of the preclinical safety assessment of novel therapeutic mAbs. One of the challenges for the development and comparison of CRA performance is the lack of availability of standard positive and negative control mAbs for use in assay qualification. To address this issue, the National Institute for Biological Standards and Control (NIBSC) developed a reference panel of lyophilised mAbs known to induce CRS in the clinic: human anti-CD52, mouse anti-CD3 and human superagonistic (SA) anti-CD28 mAb manufactured according to the respective published sequences of Campath-1H® (alemtuzumab, IgG1) , Orthoclone OKT-3® (muromonab, IgG2a) and TGN1412 (theralizumab, IgG4), as well as three isotype matched negative controls (human IgG1, mouse IgG2a and human IgG4, respectively). The relative capacity of these control mAbs to stimulate the release of IFN-γ, IL-2, TNF-α and IL-6 in vitro was evaluated in eleven laboratories in an international collaborative study mediated through the HESI Immuno-safety Technical Committee Cytokine Release Assay Working Group. Participants tested the NIBSC mAbs in a variety of CRA platforms established at each institution. This paper presents the results from the centralised cytokine quantification on all the plasma/supernatants corresponding to the stimulation of immune cells in the different CRA platforms by a single concentration of each mAb. Each positive control mAb induced significant cytokine release in most of the tested CRA platforms. There was a high inter-laboratory variability in the levels of cytokines produced, but similar patterns of response were observed across laboratories that replicated the cytokine release patterns previously published for the respective clinical therapeutic mAbs. Therefore, the positive and negative mAbs are suitable as a reference panel for the qualification and validation of CRAs, comparison of different CRA platforms (e.g. solid vs aqueous phase), and intra- and inter-laboratory comparison of CRA performance. Thus, the use of this panel of positive and negative control mAbs will increase the confidence in the robustness of a CRA platform to identify a potential CRS risk for novel immunomodulatory therapeutic candidates.
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Affiliation(s)
- Sandrine Vessillier
- National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, UK
| | - Madeline Fort
- Amgen Inc., 1120 Veterans Blvd, South San Francisco CA 94080, USA
| | - Lynn O'Donnell
- Drug Safety Research and Development, Pfizer, Inc., Groton, CT 06340, USA
| | - Heather Hinton
- Roche Innovation Center, Basel, Switzerland. Pharmaceutical Sciences Switzerland
| | - Kimberly Nadwodny
- GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
| | - Joseph Piccotti
- Bristol-Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, USA
| | - Peter Rigsby
- National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, UK
| | - Karin Staflin
- Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
| | - Richard Stebbings
- Oncology Safety, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Divya Mekala
- Janssen R&D, 1400 McKean Road, Spring House, PA 19477, USA
| | - Aarron Willingham
- MRL, Merck & Co., Inc., 213 E Grand Ave, South San Francisco, CA 94080, USA
| | - Babette Wolf
- Novartis Institutes for BioMedical Research, Klybeckstrasse 141, Basel CH-4002, Switzerland
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"Cytokine storm", not only in COVID-19 patients. Mini-review. Immunol Lett 2020; 228:38-44. [PMID: 33007369 PMCID: PMC7524442 DOI: 10.1016/j.imlet.2020.09.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/10/2020] [Accepted: 09/22/2020] [Indexed: 01/09/2023]
Abstract
Cytokine storm is a form of uncontrolled systemic inflammatory reaction activated by a variety of factors and leading to a harmful homeostatic process, even to patient's death. Triggers that start the reaction are infection, systemic diseases and rarely anaphylaxis. Cytokine storm is frequently mentioned in connection to medical interventions such as transplantation or administration of drugs. Presented mini-review would like to show current possibilities how to fight or even stop such a life-threatening, immune-mediated process in order to save lives, not only in COVID-19 patients. Early identification of rising state and multilevel course of treatment is imperative. The most widely used molecule for systemic treatment remains tocilizumab. Except for anti IL-6 treatment, contemporary research opens the possibilities for combination of pharmaceutical, non-pharmaceutical and adjunctive treatment in a successful fight with consequences of cytokine storm. Further work is needed to discover the exact signaling pathways that lead to cytokine storm and to determine how these effector molecules and/or combination of processes can help to resolve this frequently fatal episode of inflammation. It is a huge need for all scientists and clinicians to establish a physiological rational for new therapeutic targets that might lead to more personalized medicine approaches.
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Azar MM, Shin JJ, Kang I, Landry M. Diagnosis of SARS-CoV-2 infection in the setting of the cytokine release syndrome. Expert Rev Mol Diagn 2020; 20:1087-1097. [PMID: 32990479 DOI: 10.1080/14737159.2020.1830760] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Coronavirus disease (COVID-19) can trigger a cytokine response storm (CRS) that is associated with high mortality but for which the underlying pathophysiology and diagnostics are not yet well characterized. This review provides an overview of the underlying immune profile of COVID-19-related CRS as well as laboratory markers for acute diagnosis and chronic follow-up of patients with SARS-CoV-2 and CRS. AREAS COVERED Innate and acquired immune profiles in COVID-19-CRS, RNA-detection methods for SARS-CoV-2 in the setting of CRS including factors that affect assay performance, serology for SARS-CoV-2 in the setting of CRS, and other biomarkers for COVID-19 will be discussed. EXPERT OPINION Studies support the implication of CRS in the pathogenesis, clinical severity and outcome of COVID-19 through the production of multiple inflammatory cytokines and chemokines from activated innate and adaptive immune cells. Although these inflammatory molecules, including IL-6, IL-2 R, IL-10, IP-10 and MCP-1, often correlate with disease severity as possible biomarkers, the pathogenic contributions of individual molecules and the therapeutic benefits of targeting them are yet to be demonstrated. Detection of SARS-CoV-2 RNA is the gold standard method for diagnosis of COVID-19 in the context of CRS but assay performance varies and is susceptible to false-negative results even as patients clinically deteriorate due to decreased viral shedding in the setting of CRS. Biomarkers including CRP, ferritin, D-dimer and procalcitonin may provide early clues about progression to CRS and help identify thrombotic and infectious complications of COVID-19.
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Affiliation(s)
- Marwan M Azar
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine , New Haven, CT, USA
| | - Junghee J Shin
- Department of Internal Medicine, Section of Rheumatology, Allergy & Immunology, Yale School of Medicine , New Haven, CT, USA
| | - Insoo Kang
- Department of Internal Medicine, Section of Rheumatology, Allergy & Immunology, Yale School of Medicine , New Haven, CT, USA
| | - Marie Landry
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine , New Haven, CT, USA.,Department of Laboratory Medicine, Yale School of Medicine , New Haven, CT, USA
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Balhorn R, Balhorn MC. Therapeutic applications of the selective high affinity ligand drug SH7139 extend beyond non-Hodgkin's lymphoma to many other types of solid cancers. Oncotarget 2020; 11:3315-3349. [PMID: 32934776 PMCID: PMC7476732 DOI: 10.18632/oncotarget.27709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 07/27/2020] [Indexed: 01/04/2023] Open
Abstract
SH7139, the first of a series of selective high affinity ligand (SHAL) oncology drug candidates designed to target and bind to the HLA-DR proteins overexpressed by B-cell lymphomas, has demonstrated exceptional efficacy in the treatment of Burkitt lymphoma xenografts in mice and a safety profile that may prove to be unprecedented for an oncology drug. The aim of this study was to determine how frequently the HLA-DRs targeted by SH7139 are expressed by different subtypes of non-Hodgkin’s lymphoma and by other solid cancers that have been reported to express HLA-DR. Binding studies conducted with SH7129, a biotinylated analog of SH7139, reveal that more than half of the biopsy sections obtained from patients with different types of non-Hodgkin’s lymphoma express the HLA-DRs targeted by SH7139. Similar analyses of tumor biopsy tissue obtained from patients diagnosed with eighteen other solid cancers show the majority of these tumors also express the HLA-DRs targeted by SH7139. Cervical, ovarian, colorectal and prostate cancers expressed the most HLA-DR. Only a few esophageal and head and neck tumors bound the diagnostic. Within an individual’s tumor, cell to cell differences in HLA-DR target expression varied by only 2 to 3-fold while the expression levels in tumors obtained from different patients varied as much as 10 to 100-fold. The high frequency with which SH7129 was observed to bind to these cancers suggests that many patients diagnosed with B-cell lymphomas, myelomas, and other non-hematological cancers should be considered potential candidates for new therapies such as SH7139 that target HLA-DR-expressing tumors.
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Affiliation(s)
- Rod Balhorn
- SHAL Technologies Inc., Livermore, CA 94550, USA
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Lin WW, Lu YC, Chuang CH, Cheng TL. Ab locks for improving the selectivity and safety of antibody drugs. J Biomed Sci 2020; 27:76. [PMID: 32586313 PMCID: PMC7318374 DOI: 10.1186/s12929-020-00652-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023] Open
Abstract
Monoclonal antibodies (mAbs) are a major targeted therapy for malignancies, infectious diseases, autoimmune diseases, transplant rejection and chronic inflammatory diseases due to their antigen specificity and longer half-life than conventional drugs. However, long-term systemic antigen neutralization by mAbs may cause severe adverse events. Improving the selectivity of mAbs to distinguish target antigens at the disease site from normal healthy tissue and reducing severe adverse events caused by the mechanisms-of-action of mAbs is still a pressing need. Development of pro-antibodies (pro-Abs) by installing a protease-cleavable Ab lock is a novel and advanced recombinant Ab-based strategy that efficiently masks the antigen binding ability of mAbs in the normal state and selectively "turns on" the mAb activity when the pro-Ab reaches the proteolytic protease-overexpressed diseased tissue. In this review, we discuss the design and advantages/disadvantages of different Ab lock strategies, focusing particularly on spatial-hindrance-based and affinity peptide-based approaches. We expect that the development of different masking strategies for mAbs will benefit the local reactivity of mAbs at the disease site, increase the therapeutic efficacy and safety of long-term treatment with mAbs in chronic diseases and even permit scientists to develop Ab drugs for formerly undruggable targets and satisfy the unmet medical needs of mAb therapy.
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Affiliation(s)
- Wen-Wei Lin
- Department of Laboratory Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yun-Chi Lu
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan
| | - Chih-Hung Chuang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tian-Lu Cheng
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan.
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Freeman TL, Swartz TH. Targeting the NLRP3 Inflammasome in Severe COVID-19. Front Immunol 2020; 11:1518. [PMID: 32655582 PMCID: PMC7324760 DOI: 10.3389/fimmu.2020.01518] [Citation(s) in RCA: 318] [Impact Index Per Article: 63.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 06/09/2020] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1β. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.
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MESH Headings
- Animals
- Betacoronavirus/metabolism
- COVID-19
- Coronavirus Infections/complications
- Coronavirus Infections/drug therapy
- Coronavirus Infections/metabolism
- Coronavirus Infections/virology
- Cytokine Release Syndrome/drug therapy
- Cytokine Release Syndrome/metabolism
- Furans
- Heterocyclic Compounds, 4 or More Rings/pharmacology
- Heterocyclic Compounds, 4 or More Rings/therapeutic use
- Humans
- Immunity, Innate
- Indenes
- Inflammasomes/antagonists & inhibitors
- Inflammasomes/metabolism
- Interleukin 1 Receptor Antagonist Protein/pharmacology
- Interleukin 1 Receptor Antagonist Protein/therapeutic use
- Interleukin-1beta/antagonists & inhibitors
- Interleukin-1beta/metabolism
- Mice
- NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors
- NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
- Pandemics
- Pneumonia, Viral/complications
- Pneumonia, Viral/drug therapy
- Pneumonia, Viral/metabolism
- Pneumonia, Viral/virology
- Pyroptosis/drug effects
- Respiratory Distress Syndrome/drug therapy
- Respiratory Distress Syndrome/etiology
- Respiratory Distress Syndrome/metabolism
- SARS-CoV-2
- Sesquiterpenes, Guaiane/pharmacology
- Sesquiterpenes, Guaiane/therapeutic use
- Sulfonamides
- Sulfones/pharmacology
- Sulfones/therapeutic use
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Affiliation(s)
| | - Talia H. Swartz
- Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Regulatory and strategic considerations for addressing immunogenicity and related responses in biopharmaceutical development programs. J Clin Transl Sci 2020; 4:547-555. [PMID: 33948231 PMCID: PMC8057416 DOI: 10.1017/cts.2020.493] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The last three decades have seen the biotherapeutic drug market evolve from promising concept to market dominance in a range of clinical indications. This growth has been spurred by the success of established drug classes like monoclonal antibodies, but also by the introduction of biosimilars, and more recently, multiple novel cell and gene therapies. Biotherapeutic drug development presents many unique challenges, but unintended immune responses are among the most common reasons for program attrition. Anti-drug antibodies can impact the safety and efficacy of drug products, and related immune responses, like the cytokine release syndrome that occurred in the infamous TGN-1412 clinical trial, can be challenging to predict with nonclinical models. For this reason, it is important that development programs proceed with a scientifically grounded and measured approach to these responses. This process begins at the discovery stage with the application of “quality by design,” continues into the clinic with the development of quality assays and management strategies, and culminates in the effective presentation of this information in regulatory documents. This review provides an overview of some of the key strategic and regulatory considerations for biotherapeutics as they pertain to immunogenicity and related responses.
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CD56bright Natural Killer Cells: A Possible Biomarker of Different Treatments in Multiple Sclerosis. J Clin Med 2020; 9:jcm9051450. [PMID: 32414131 PMCID: PMC7291063 DOI: 10.3390/jcm9051450] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/05/2020] [Accepted: 05/08/2020] [Indexed: 12/11/2022] Open
Abstract
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, which leads, in many cases, to irreversible disability. More than 15 disease-modifying treatments (DMTs) are available for the treatment of MS. Clinical activity or activity at magnetic resonance imaging (MRI) are now used to assess the efficacy of DMTs, but are negative prognostic factors per se. Therefore, a biomarker permitting us to identify patients who respond to treatment before they develop clinical/radiological signs of MS activity would be of high importance. The number of circulating CD56bright natural killer (NK) cells may be such a biomarker. CD56bright NK cells are a regulatory immune population belonging to the innate immune system. The number of CD56bright NK cells increases upon treatment with interferon-beta, alemtuzumab, dimethyl fumarate, after autologous hematopoietic stem cell transplantation, and is higher in those who respond to fingolimod. In some cases, an increased number of CD56bright NK cells is associated with an increase in their regulatory function. In the current review, we will evaluate the known effect on CD56bright NK cells of DMTs for MS, and will discuss their possible role as a biomarker for treatment response in MS.
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36
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Soleimani B, Murray K, Hunt D. Established and Emerging Immunological Complications of Biological Therapeutics in Multiple Sclerosis. Drug Saf 2020; 42:941-956. [PMID: 30830572 DOI: 10.1007/s40264-019-00799-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Biologic immunotherapies have transformed the treatment landscape of multiple sclerosis. Such therapies include recombinant proteins (interferon beta), as well as monoclonal antibodies (natalizumab, alemtuzumab, daclizumab, rituximab and ocrelizumab). Monoclonal antibodies show particular efficacy in the treatment of the inflammatory phase of multiple sclerosis. However, the immunological perturbations caused by biologic therapies are associated with significant immunological adverse reactions. These include development of neutralising immunogenicity, secondary immunodeficiency and secondary autoimmunity. These complications can affect the balance of risks and benefits of biologic agents, and 2018 saw the withdrawal from the market of daclizumab, an anti-CD25 monoclonal antibody, due to concerns about the development of severe, unpredictable autoimmunity. Here we review established and emerging risks associated with multiple sclerosis biologic agents, with an emphasis on their immunological adverse effects. We also discuss the specific challenges that multiple sclerosis biologics pose to drug safety systems, and the potential for improvements in safety frameworks.
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Affiliation(s)
| | - Katy Murray
- Anne Rowling Clinic, University of Edinburgh, Edinburgh, UK
| | - David Hunt
- Anne Rowling Clinic, University of Edinburgh, Edinburgh, UK. .,MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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Be aware that the benefits of biological drugs in multiple sclerosis may be offset by their capacity to cause immunological complications. DRUGS & THERAPY PERSPECTIVES 2020. [DOI: 10.1007/s40267-019-00693-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Holmøy T, Fevang B, Olsen DB, Spigset O, Bø L. Adverse events with fatal outcome associated with alemtuzumab treatment in multiple sclerosis. BMC Res Notes 2019; 12:497. [PMID: 31405369 PMCID: PMC6689881 DOI: 10.1186/s13104-019-4507-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 07/20/2019] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. RESULTS We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment.
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Affiliation(s)
- Trygve Holmøy
- Department of Neurology, Akershus University Hospital, Post Office Box 1000, 1478, Lørenskog, Norway. .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Børre Fevang
- Centre for Rare Disorders, Oslo University Hospital, Sognsvannsveien 20, 0372, Oslo, Norway.,Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Sognsvannsveien 20, 0372, Oslo, Norway
| | - David Benee Olsen
- Department of Pharmacovigilance, Norwegian Medicines Agency, Post Office Box 240, Skøyen, 0213, Oslo, Norway
| | - Olav Spigset
- Department of Clinical Pharmacology, St. Olavs University Hospital, Post Office Box 3250, Torgarden, 7006, Trondheim, Norway.,Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Lars Bø
- Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Post Office Box 1400, 5021, Bergen, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
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See Hoe LE, Bartnikowski N, Wells MA, Suen JY, Fraser JF. Hurdles to Cardioprotection in the Critically Ill. Int J Mol Sci 2019; 20:E3823. [PMID: 31387264 PMCID: PMC6695809 DOI: 10.3390/ijms20153823] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 07/26/2019] [Accepted: 08/03/2019] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease is the largest contributor to worldwide mortality, and the deleterious impact of heart failure (HF) is projected to grow exponentially in the future. As heart transplantation (HTx) is the only effective treatment for end-stage HF, development of mechanical circulatory support (MCS) technology has unveiled additional therapeutic options for refractory cardiac disease. Unfortunately, despite both MCS and HTx being quintessential treatments for significant cardiac impairment, associated morbidity and mortality remain high. MCS technology continues to evolve, but is associated with numerous disturbances to cardiac function (e.g., oxidative damage, arrhythmias). Following MCS intervention, HTx is frequently the destination option for survival of critically ill cardiac patients. While effective, donor hearts are scarce, thus limiting HTx to few qualifying patients, and HTx remains correlated with substantial post-HTx complications. While MCS and HTx are vital to survival of critically ill cardiac patients, cardioprotective strategies to improve outcomes from these treatments are highly desirable. Accordingly, this review summarizes the current status of MCS and HTx in the clinic, and the associated cardiac complications inherent to these treatments. Furthermore, we detail current research being undertaken to improve cardiac outcomes following MCS/HTx, and important considerations for reducing the significant morbidity and mortality associated with these necessary treatment strategies.
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Affiliation(s)
- Louise E See Hoe
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia.
- Faculty of Medicine, University of Queensland, Chermside 4032, Australia.
| | - Nicole Bartnikowski
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- Science and Engineering Faculty, Queensland University of Technology, Chermside 4032, Australia
| | - Matthew A Wells
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- School of Medical Science, Griffith University, Southport 4222, Australia
| | - Jacky Y Suen
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- Faculty of Medicine, University of Queensland, Chermside 4032, Australia
| | - John F Fraser
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- Faculty of Medicine, University of Queensland, Chermside 4032, Australia
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Hunter BD, Rogalski M, Jacobson CA. Chimeric antigen receptor T-cell therapy for the treatment of aggressive B-cell non-Hodgkin lymphomas: efficacy, toxicity, and comparative chimeric antigen receptor products. Expert Opin Biol Ther 2019; 19:1157-1164. [DOI: 10.1080/14712598.2019.1644316] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Bradley D. Hunter
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Michael Rogalski
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Caron A. Jacobson
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
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The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. Nat Commun 2019; 10:2235. [PMID: 31138805 PMCID: PMC6538754 DOI: 10.1038/s41467-019-10043-0] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 04/16/2019] [Indexed: 12/17/2022] Open
Abstract
Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).
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42
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Kang B, Park H, Kim B. Anticancer Activity and Underlying Mechanism of Phytochemicals against Multiple Myeloma. Int J Mol Sci 2019; 20:E2302. [PMID: 31075954 PMCID: PMC6539572 DOI: 10.3390/ijms20092302] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/03/2019] [Accepted: 05/04/2019] [Indexed: 12/14/2022] Open
Abstract
Multiple myeloma (MM)-a common hematologic malignancy of plasma cells-accounts for substantial mortality and morbidity rates. Due to the advent of novel therapies such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs), response rates were increased and free survival and overall survival have been elevated. However, adverse events including toxicity, neuropathy or continuous relapse are still problems. Thus, development of novel drugs which have less side effects and more effective is needed. This review aims to recapitulate the pharmacologic anti-MM mechanisms of various phytochemicals, elucidating their molecular targets. Keywords related to MM and natural products were searched in PUBMED/MEDLINE. Phytochemicals have been reported to display a variety of anti-MM activities, including apoptosis, cell cycle arrest, antiangiogenesis, and miRNA modulation. Some phytochemicals sensitize the conventional therapies such as dexamethasone. Also, there are clinical trials with phytochemicals such as agaricus, curcumin, and Neovastat regarding MM treatment. Taken together, this review elucidated and categorized the evidences that natural products and their bioactive compounds could be potent drugs in treating MM.
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Affiliation(s)
- Beomku Kang
- College of Korean Medicine, Kyung Hee University, Seoul 02453, Korea.
| | - Hyunmin Park
- Department of Pathology, College of Korean Medicine, Graduate School, Kyung Hee University, Seoul 02453, Korea.
| | - Bonglee Kim
- College of Korean Medicine, Kyung Hee University, Seoul 02453, Korea.
- Department of Pathology, College of Korean Medicine, Graduate School, Kyung Hee University, Seoul 02453, Korea.
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Garcia Borrega J, Gödel P, Rüger MA, Onur ÖA, Shimabukuro-Vornhagen A, Kochanek M, Böll B. In the Eye of the Storm: Immune-mediated Toxicities Associated With CAR-T Cell Therapy. Hemasphere 2019; 3:e191. [PMID: 31723828 PMCID: PMC6746039 DOI: 10.1097/hs9.0000000000000191] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 02/15/2019] [Accepted: 02/15/2019] [Indexed: 12/16/2022] Open
Abstract
The success of chimeric antigen receptor (CAR)-T cell therapy with impressive response rates in hematologic malignancies but also promising data in solid tumors came along with the cognition of unexpected, potentially life-threatening immune-mediated toxicities, namely the cytokine release syndrome (CRS) and neurotoxicity recently referred to as "immune effector cell-associated neurotoxicity syndrome" (ICANS). These toxicities require urgent diagnostic and therapeutic interventions and targeted modulation of key cytokine pathways represents the mainstay of CRS treatment. However, as the underlying mechanisms of ICANS are not well understood, treatment options remain limited and further investigation is warranted. Importantly, after the recent market approval of 2 CAR-T cell constructs, the application of CAR-T cells will expand to nonacademic centers with limited experience in the management of CAR-T cell-associated toxicities. Here, we review the current evidence of CRS and ICANS pathophysiology, diagnostics, and treatment.
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Affiliation(s)
- Jorge Garcia Borrega
- Department I of Internal Medicine, Hematology-Oncology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Cologne, Cologne, Germany
- Intensive Care Program, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
| | - Philipp Gödel
- Department I of Internal Medicine, Hematology-Oncology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Cologne, Cologne, Germany
- Intensive Care Program, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Cologne Translational Immunology, University Hospital of Cologne, Cologne, Germany
| | - Maria Adele Rüger
- Department of Neurology, University Hospital of Cologne, Cologne, Germany
| | - Özgür A. Onur
- Department of Neurology, University Hospital of Cologne, Cologne, Germany
| | - Alexander Shimabukuro-Vornhagen
- Department I of Internal Medicine, Hematology-Oncology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Cologne, Cologne, Germany
- Intensive Care Program, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Intensive Care in HematoOncologic Patients (iCHOP) Collaborative Group
| | - Matthias Kochanek
- Department I of Internal Medicine, Hematology-Oncology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Cologne, Cologne, Germany
- Intensive Care Program, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Intensive Care in HematoOncologic Patients (iCHOP) Collaborative Group
| | - Boris Böll
- Department I of Internal Medicine, Hematology-Oncology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Cologne, Cologne, Germany
- Intensive Care Program, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Intensive Care in HematoOncologic Patients (iCHOP) Collaborative Group
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Monoclonal Antibodies in Multiple Sclerosis: Present and Future. Biomedicines 2019; 7:biomedicines7010020. [PMID: 30875812 PMCID: PMC6466331 DOI: 10.3390/biomedicines7010020] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 03/11/2019] [Accepted: 03/11/2019] [Indexed: 01/09/2023] Open
Abstract
The global incidence of multiple sclerosis (MS) appears to be increasing. Although it may not be associated with a high mortality rate, this disease has a high morbidity rate which affects the quality of life of patients and reduces their ability to do their activities of daily living. Thankfully, the development of novel disease modifying therapies continues to increase. Monoclonal antibodies (MABs) have become a mainstay of MS treatment and they are likely to continue to be developed for the treatment of this disease. Specifically, MABs have proven to be some of the most efficacious treatments at reducing relapses and the inflammation in MS patients, including the first treatment for primary progressive MS and are being explored as reparative/remyelinating agents as well. These relatively new treatments will be reviewed here to help evaluate their efficacy, adverse events, immunogenicity, and benefit-risk ratios in the treatment of the diverse spectrum of MS. The focus will be on MABs that are currently approved or may be approved in the near future.
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Hussain K, Hargreaves CE, Rowley TF, Sopp JM, Latham KV, Bhatta P, Sherington J, Cutler RM, Humphreys DP, Glennie MJ, Strefford JC, Cragg MS. Impact of Human FcγR Gene Polymorphisms on IgG-Triggered Cytokine Release: Critical Importance of Cell Assay Format. Front Immunol 2019; 10:390. [PMID: 30899264 PMCID: PMC6417454 DOI: 10.3389/fimmu.2019.00390] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 02/14/2019] [Indexed: 12/17/2022] Open
Abstract
Monoclonal antibody (mAb) immunotherapy has transformed the treatment of allergy, autoimmunity, and cancer. The interaction of mAb with Fc gamma receptors (FcγR) is often critical for efficacy. The genes encoding the low-affinity FcγR have single nucleotide polymorphisms (SNPs) and copy number variation that can impact IgG Fc:FcγR interactions. Leukocyte-based in vitro assays remain one of the industry standards for determining mAb efficacy and predicting adverse responses in patients. Here we addressed the impact of FcγR genetics on immune cell responses in these assays and investigated the importance of assay format. FcγR genotyping of 271 healthy donors was performed using a Multiplex Ligation-Dependent Probe Amplification assay. Freeze-thawed/pre-cultured peripheral blood mononuclear cells (PBMCs) and whole blood samples from donors were stimulated with reagents spanning different mAb functional classes to evaluate the association of FcγR genotypes with T-cell proliferation and cytokine release. Using freeze-thawed/pre-cultured PBMCs, agonistic T-cell-targeting mAb induced T-cell proliferation and the highest levels of cytokine release, with lower but measurable responses from mAb which directly require FcγR-mediated cellular effects for function. Effects were consistent for individual donors over time, however, no significant associations with FcγR genotypes were observed using this assay format. In contrast, significantly elevated IFN-γ release was associated with the FCGR2A-131H/H genotype compared to FCGR2A-131R/R in whole blood stimulated with Campath (p ≤ 0.01) and IgG1 Fc hexamer (p ≤ 0.05). Donors homozygous for both the high affinity FCGR2A-131H and FCGR3A-158V alleles mounted stronger IFN-γ responses to Campath (p ≤ 0.05) and IgG1 Fc Hexamer (p ≤ 0.05) compared to donors homozygous for the low affinity alleles. Analysis revealed significant reductions in the proportion of CD14hi monocytes, CD56dim NK cells (p ≤ 0.05) and FcγRIIIa expression (p ≤ 0.05), in donor-matched freeze-thawed PBMC compared to whole blood samples, likely explaining the difference in association between FcγR genotype and mAb-mediated cytokine release in the different assay formats. These findings highlight the significant impact of FCGR2A and FCGR3A SNPs on mAb function and the importance of using fresh whole blood assays when evaluating their association with mAb-mediated cytokine release in vitro. This knowledge can better inform on the utility of in vitro assays for the prediction of mAb therapy outcome in patients.
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Affiliation(s)
- Khiyam Hussain
- Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Chantal E. Hargreaves
- Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
- Cancer Genomics Group, Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | | | - Joshua M. Sopp
- Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Kate V. Latham
- Cancer Genomics Group, Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | | | | | | | | | - Martin J. Glennie
- Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Jonathan C. Strefford
- Cancer Genomics Group, Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Mark S. Cragg
- Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
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Del Bufalo F, Merli P, Alessi I, Locatelli F. B-cell depleting immunotherapies: therapeutic opportunities and toxicities. Expert Rev Clin Immunol 2019; 15:497-509. [PMID: 30681371 DOI: 10.1080/1744666x.2019.1573672] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The last few years have witnessed what can certainly be defined as a 'period of renaissance' for immunotherapy in the field of hematological malignancies. In particular, antibody-mediated and cell-mediated immunotherapy have significantly changed the treatment approach of patients with B-cell lymphoproliferative disorders. These therapies, initially employed in patients with refractory/relapsed disease, are now integrated in the treatment of newly diagnosed patients. Together with the therapeutic success, we have also learnt that these innovative therapies can induce relevant, sometimes life-threatening or even fatal, side effects. Areas covered: In this review article, we analyzed the applicative therapeutic scenario and the peculiar toxicities associated with approaches of immunotherapy, paying particular attention to the new emerging side effects, substantially unknown before the introduction of these therapies. Expert commentary: Both monoclonal antibodies and cell therapy with lymphocytes genetically modified to be redirected against leukemia targets through the transduction with chimeric antigen receptors (CARs) have obtained unprecedented success in rescuing patients with resistant B-cell malignancies. Complications, such as neurotoxicity, cytokine release syndrome or persistent B-cell lymphopenia, must always be taken into consideration and diagnosed in a timely manner in patients with B-cell neoplasms to guarantee optimal management, thus avoiding they blunting the efficacy of immunotherapy.
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Affiliation(s)
- Francesca Del Bufalo
- a Department of Pediatric Hematology and Oncology, Cellular and Gene Therapy , IRCCS Ospedale Pediatrico Bambino Gesù , Rome , Italy
| | - Pietro Merli
- a Department of Pediatric Hematology and Oncology, Cellular and Gene Therapy , IRCCS Ospedale Pediatrico Bambino Gesù , Rome , Italy
| | - Iside Alessi
- a Department of Pediatric Hematology and Oncology, Cellular and Gene Therapy , IRCCS Ospedale Pediatrico Bambino Gesù , Rome , Italy
| | - Franco Locatelli
- a Department of Pediatric Hematology and Oncology, Cellular and Gene Therapy , IRCCS Ospedale Pediatrico Bambino Gesù , Rome , Italy.,b Department of Pediatrics , Sapienza University of Rome , Rome , Italy
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Nye CJS, Wagner A, Kousin-Ezewu O, Jones JL, Coles AJ. A case of anaphylaxis to alemtuzumab. J Neurol 2019; 266:780-781. [DOI: 10.1007/s00415-019-09214-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 01/22/2019] [Indexed: 10/27/2022]
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49
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Pfeuffer S, Schmidt R, Straeten FA, Pul R, Kleinschnitz C, Wieshuber M, Lee DH, Linker RA, Doerck S, Straeten V, Windhagen S, Pawlitzki M, Aufenberg C, Lang M, Eienbroeker C, Tackenberg B, Limmroth V, Wildemann B, Haas J, Klotz L, Wiendl H, Ruck T, Meuth SG. Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation. J Neurol 2018; 266:165-173. [DOI: 10.1007/s00415-018-9117-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 11/04/2018] [Accepted: 11/08/2018] [Indexed: 10/27/2022]
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50
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Katsavos S, Coles A. Alemtuzumab as Treatment for Multiple Sclerosis. Cold Spring Harb Perspect Med 2018; 8:cshperspect.a032029. [PMID: 29500306 DOI: 10.1101/cshperspect.a032029] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Alemtuzumab, the first monoclonal antibody to be used as a therapy and the first to be humanized, was introduced into the treatment of multiple sclerosis in 1991 after its successful use in hematology, oncology, and transplantation medicine. One phase 2 and two phase 3 trials of this lymphocyte-depleting agent have established alemtuzumab's superior efficacy to interferon β-1a over the short term (2-3 years) with greater relapse rate reduction, reduced accumulation of disability, and more frequent sustained improvement in disability. Longer-term extension studies show durable effects on slowing cerebral atrophy over 6 years and maintained low relapse rates over 10 years, despite roughly half of patients not needing further dosing. Homeostatic proliferation of residual T cells after alemtuzumab-induced lymphopenia is probably responsible for its most common side effects: secondary autoimmunity 1 or 2 years after the last infusion of alemtuzumab affecting the thyroid gland (30% of patients), platelets (1%), or renal glomeruli (0.1%). With the prerequisite of patient and physician adherence to a prolonged safety-monitoring protocol, alemtuzumab offers durable high efficacy from infrequent dosing.
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Affiliation(s)
- Serafeim Katsavos
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, United Kingdom
| | - Alasdair Coles
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, United Kingdom
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