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Bayat M, Nahand JS. Battlegrounds of treatment resistance: decoding the tumor microenvironment. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04055-5. [PMID: 40131387 DOI: 10.1007/s00210-025-04055-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025]
Abstract
The tumor microenvironment (TME) emerges as a formidable actor in the cancer treatment landscape, wielding the power to thwart therapeutic efficacy across various modalities, including chemotherapy, radiotherapy, immunotherapy, targeted therapy, and hormonal therapy. This intricate ecosystem comprising diverse cellular constituents, signaling molecules, and the extracellular matrix fosters a dynamic interplay that profoundly influences tumor behavior and treatment outcomes. This review explores the mechanisms through which the TME drives resistance to standard therapies, emphasizing key factors such as hypoxia, immune evasion, and metabolic reprogramming. Furthermore, we illuminate innovative strategies aimed at reprogramming this hostile environment, including the application of therapeutic vaccines, CAR T cell therapy, and combination immunotherapies designed to enhance anti-tumor responses. By advocating for multidimensional approaches that dismantle the TME's barriers to effective treatment, this review calls for a transformative shift in cancer treatment paradigms. By bridging the gap between the TME's complexities and targeted therapeutic strategies, we pave the way for targeted interventions that promise to enhance clinical outcomes and improve patient prognosis in the relentless battle against cancer.
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Affiliation(s)
- Mobina Bayat
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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2
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Du W, Na J, Zhong L, Zhang P. Advances in preclinical and clinical studies of oncolytic virus combination therapy. Front Oncol 2025; 15:1545542. [PMID: 39990685 PMCID: PMC11842258 DOI: 10.3389/fonc.2025.1545542] [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: 12/15/2024] [Accepted: 01/09/2025] [Indexed: 02/25/2025] Open
Abstract
Oncolytic viruses represent a distinct class of viruses that selectively infect and destroy tumor cells while sparing normal cells. Despite their potential, oncolytic viruses encounter several challenges as standalone therapies. Consequently, the combination of oncolytic viruses with other therapeutic modalities has emerged as a prominent research focus. This paper summarizes the tumor-killing mechanisms of oncolytic viruses, explores their integration with radiotherapy, chemotherapy, immune checkpoint inhibitors, CAR-T, and CAR-NK therapies, and provides an overview of related clinical trials. By synthesizing these advancements, this study seeks to offer valuable insights for the clinical translation of oncolytic virus combination therapies.
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Affiliation(s)
- Wenlong Du
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning, China
| | - Jintong Na
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning, China
| | - Liping Zhong
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning, China
- Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China
| | - Pumin Zhang
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning, China
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3
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Bo Y, Wang H. Biomaterial-Based In Situ Cancer Vaccines. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2210452. [PMID: 36649567 PMCID: PMC10408245 DOI: 10.1002/adma.202210452] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/06/2023] [Indexed: 06/17/2023]
Abstract
Cancer immunotherapies have reshaped the paradigm for cancer treatment over the past decade. Among them, therapeutic cancer vaccines that aim to modulate antigen-presenting cells and subsequent T cell priming processes are among the first FDA-approved cancer immunotherapies. However, despite showing benign safety profiles and the capability to generate antigen-specific humoral and cellular responses, cancer vaccines have been limited by the modest therapeutic efficacy, especially for immunologically cold solid tumors. One key challenge lies in the identification of tumor-specific antigens, which involves a costly and lengthy process of tumor cell isolation, DNA/RNA extraction, sequencing, mutation analysis, epitope prediction, peptide synthesis, and antigen screening. To address these issues, in situ cancer vaccines have been actively pursued to generate endogenous antigens directly from tumors and utilize the generated tumor antigens to elicit potent cytotoxic T lymphocyte (CTL) response. Biomaterials-based in situ cancer vaccines, in particular, have achieved significant progress by taking advantage of biomaterials that can synergize antigens and adjuvants, troubleshoot delivery issues, home, and manipulate immune cells in situ. This review will provide an overview of biomaterials-based in situ cancer vaccines, either living or artificial materials, under development or in the clinic, and discuss the design criteria for in situ cancer vaccines.
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Affiliation(s)
- Yang Bo
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Hua Wang
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Cancer Center at Illinois (CCIL), Urbana, IL, 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Carle College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
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Su M, Chen L, Xie L, Fleurie A, Jonquieres R, Cao Q, Li B, Liang J, Tang Y. Identification of early predictive biomarkers for severe cytokine release syndrome in pediatric patients with chimeric antigen receptor T-cell therapy. Front Immunol 2024; 15:1450173. [PMID: 39328408 PMCID: PMC11424402 DOI: 10.3389/fimmu.2024.1450173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 08/26/2024] [Indexed: 09/28/2024] Open
Abstract
CAR-T cell therapy is a revolutionary new treatment for hematological malignancies, but it can also result in significant adverse effects, with cytokine release syndrome (CRS) being the most common and potentially life-threatening. The identification of biomarkers to predict the severity of CRS is crucial to ensure the safety and efficacy of CAR-T therapy. To achieve this goal, we characterized the expression profiles of seven cytokines, four conventional biochemical markers, and five hematological markers prior to and following CAR-T cell infusion. Our results revealed that IL-2, IFN-γ, IL-6, and IL-10 are the key cytokines for predicting severe CRS (sCRS). Notably, IL-2 levels rise at an earlier stage of sCRS and have the potential to serve as the most effective cytokine for promptly detecting the condition's onset. Furthermore, combining these cytokine biomarkers with hematological factors such as lymphocyte counts can further enhance their predictive performance. Finally, a predictive tree model including lymphocyte counts, IL-2, and IL-6 achieved an accuracy of 85.11% (95% CI = 0.763-0.916) for early prediction of sCRS. The model was validated in an independent cohort and achieved an accuracy of 74.47% (95% CI = 0.597-0.861). This new prediction model has the potential to become an effective tool for assessing the risk of CRS in clinical practice.
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Affiliation(s)
- Meng Su
- Department of Hematology/Oncology, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Luoquan Chen
- Shanghai Children's Medical Center-bioMérieux Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- bioMérieux (Shanghai) Company Limited, Shanghai, China
| | - Li Xie
- Shanghai Children's Medical Center-bioMérieux Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- bioMérieux (Shanghai) Company Limited, Shanghai, China
| | - Aurore Fleurie
- Open Innovation & Partnerships Department, bioMérieux SA, Marcy l'Etoile, France
| | - Renaud Jonquieres
- Open Innovation & Partnerships Department, bioMérieux SA, Marcy l'Etoile, France
| | - Qing Cao
- Infectious Disease Department, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Benshang Li
- Department of Hematology/Oncology, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ji Liang
- Shanghai Children's Medical Center-bioMérieux Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- bioMérieux (Shanghai) Company Limited, Shanghai, China
| | - Yanjing Tang
- Department of Hematology/Oncology, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Jia G, Fu L, Wang L, Yao D, Cui Y. Bayesian network analysis of risk classification strategies in the regulation of cellular products. Artif Intell Med 2024; 155:102937. [PMID: 39137589 DOI: 10.1016/j.artmed.2024.102937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 07/03/2024] [Accepted: 07/26/2024] [Indexed: 08/15/2024]
Abstract
Cell therapy, a burgeoning therapeutic strategy, necessitates a scientific regulatory framework but faces challenges in risk-based regulation due to the lack of a global consensus on risk classification. This study applies Bayesian network analysis to compare and evaluate the risk classification strategies for cellular products proposed by the Food and Drug Administration (FDA), Ministry of Health, Labour and Welfare (MHLW), and World Health Organization (WHO), using real-world data to validate the models. The appropriateness of key risk factors is assessed within the three regulatory frameworks, along with their implications for clinical safety. The results indicate several directions for refining risk classification approaches. Additionally, a substudy focuses on a specific type of cell and gene therapy (CGT), chimeric antigen receptor (CAR) T cell therapy. It underscores the importance of considering CAR targets, tumor types, and costimulatory domains when assessing the safety risks of CAR T cell products. Overall, there is currently a lack of a regulatory framework based on real-world data for cellular products and a lack of risk-based classification review methods. This study aims to improve the regulatory system for cellular products, emphasizing risk-based classification. Furthermore, the study advocates for leveraging machine learning in regulatory science to enhance the assessment of cellular product safety, illustrating the role of Bayesian networks in aiding regulatory decision-making for the risk classification of cellular products.
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Affiliation(s)
- Guoshu Jia
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100034, China; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing 211198, China
| | - Lixia Fu
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100034, China; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Likun Wang
- Department of Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Dongning Yao
- School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Yimin Cui
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100034, China; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
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Sharma S, Mehta NU, Sauer T, Rollins LA, Dittmer DP, Rooney CM. Cotargeting EBV lytic as well as latent cycle antigens increases T-cell potency against lymphoma. Blood Adv 2024; 8:3360-3371. [PMID: 38640255 PMCID: PMC11255116 DOI: 10.1182/bloodadvances.2023012183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/20/2024] [Accepted: 04/08/2024] [Indexed: 04/21/2024] Open
Abstract
ABSTRACT The remarkable efficacy of Epstein-Barr virus (EBV)-specific T cells for the treatment of posttransplant lymphomas has not been reproduced for EBV-positive (EBV+) malignancies outside the transplant setting. This is because of, in part, the heterogeneous expression and poor immunogenicity of the viral antigens expressed, namely latent membrane proteins 1 and 2, EBV nuclear antigen 1, and BamHI A rightward reading frame 1 (type-2 [T2] latency). However, EBV lytic cycle proteins are also expressed in certain EBV+ malignancies and, because several EBV lytic cycle proteins are abundantly expressed, have oncogenic activity, and likely contribute to malignancy, we sought and identified viral lytic-cycle transcripts in EBV+ Hodgkin lymphoma biopsies. This provided the rationale for broadening the target antigen-specific repertoire of EBV-specific T cells (EBVSTs) for therapy. We stimulated, peripheral blood mononuclear cells from healthy donors and patients with EBV+ lymphoma with both lytic and latent cycle proteins to produce broad repertoire (BR) EBVSTs. Compared with T2 antigen-specific EBVSTs, BR-EBVSTs more rapidly cleared autologous EBV+ tumors in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice and produced higher levels of proinflammatory cytokines that should reactivate the immunosuppressive tumor microenvironment leading to epitope spreading. Our results confirm that lytic cycle antigens are clinically relevant targets for EBV+ lymphoma and underpin the rationale for integrating BR-EBVSTs as a therapeutic approach for relapsed/refractory EBV+ lymphoma (www.clinicaltrials.gov identifiers: #NCT01555892 and #NCT04664179), as well as for other EBV-associated malignancies.
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Affiliation(s)
- Sandhya Sharma
- Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital, Houston, TX
| | - Naren U. Mehta
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital, Houston, TX
| | - Tim Sauer
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital, Houston, TX
| | - Lisa A. Rollins
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital, Houston, TX
| | - Dirk P. Dittmer
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Cliona M. Rooney
- Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital, Houston, TX
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX
- Department of Pathology-Immunology, Baylor College of Medicine, Houston, TX
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7
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Boretti A. Improving chimeric antigen receptor T-cell therapies by using artificial intelligence and internet of things technologies: A narrative review. Eur J Pharmacol 2024; 974:176618. [PMID: 38679117 DOI: 10.1016/j.ejphar.2024.176618] [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: 01/20/2024] [Revised: 04/18/2024] [Accepted: 04/25/2024] [Indexed: 05/01/2024]
Abstract
Cancer poses a formidable challenge in the field of medical science, prompting the exploration of innovative and efficient treatment strategies. One revolutionary breakthrough in cancer therapy is Chimeric Antigen Receptor (CAR) T-cell therapy, an avant-garde method involving the customization of a patient's immune cells to combat cancer. Particularly successful in addressing blood cancers, CAR T-cell therapy introduces an unprecedented level of effectiveness, offering the prospect of sustained disease management. As ongoing research advances to overcome current challenges, CAR T-cell therapy stands poised to become an essential tool in the fight against cancer. Ongoing enhancements aim to improve its effectiveness and reduce time and cost, with the integration of Artificial Intelligence (AI) and Internet of Things (IoT) technologies. The synergy of AI and IoT could enable more precise tailoring of CAR T-cell therapy to individual patients, streamlining the therapeutic process. This holds the potential to elevate treatment efficacy, mitigate adverse effects, and expedite the overall progress of CAR T-cell therapies.
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Affiliation(s)
- Alberto Boretti
- Independent Scientist, Johnsonville, Wellington, New Zealand.
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8
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Sun Z, Wang C, Zhao Y, Ling Q. CAR-T cell therapy in advanced thyroid cancer: from basic to clinical. Front Immunol 2024; 15:1411300. [PMID: 38911868 PMCID: PMC11190081 DOI: 10.3389/fimmu.2024.1411300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 05/27/2024] [Indexed: 06/25/2024] Open
Abstract
The majority of patients with thyroid cancer can attain a favorable prognosis with a comprehensive treatment program based on surgical treatment. However, the current treatment options for advanced thyroid cancer are still limited. In recent years, chimeric antigen receptor-modified T-cell (CAR-T) therapy has received widespread attention in the field of oncology treatment. It has achieved remarkable results in the treatment of hematologic tumors. However, due to the constraints of multiple factors, the therapeutic efficacy of CAR-T therapy for solid tumors, including thyroid cancer, has not yet met expectations. This review outlines the fundamental structure and treatment strategies of CAR-T cells, provides an overview of the advancements in both preclinical investigations and clinical trials focusing on targets associated with CAR-T cell therapy in treating thyroid cancer, and discusses the challenges and solutions to CAR-T cell therapy for thyroid cancer. In conclusion, CAR-T cell therapy is a promising therapeutic approach for thyroid cancer, and we hope that our review will provide a timely and updated study of CAR-T cell therapy for thyroid cancer to advance the field.
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Leland P, Degheidy H, Lea A, Bauer SR, Puri RK, Joshi BH. Identification and characterisation of novel CAR-T cells to target IL13Rα2 positive human glioma in vitro and in vivo. Clin Transl Med 2024; 14:e1664. [PMID: 38685487 PMCID: PMC11058282 DOI: 10.1002/ctm2.1664] [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: 12/16/2023] [Revised: 04/02/2024] [Accepted: 04/04/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Previously, we discovered that human solid tumours, but not normal human tissues, preferentially overexpress interleukin-13Receptor alpha2, a high binding receptor for IL-13. To develop novel anti-cancer approaches, we constructed a chimeric antigen receptor construct using a high binding and codon optimised scFv-IL-13Rα2 fragment fused with CD3ζ and co-stimulatory cytoplasmic domains of CD28 and 4-1BB. METHODS We developed a scFv clone, designated 14-1, by biopanning the bound scFv phages using huIL-13Rα2Fc chimeric protein and compared its binding with our previously published clone 4-1. We performed bioinformatic analyses for complementary determining regions (CDR) framework and residue analyses of the light and heavy chains. This construct was packaged with helper plasmids to produce CAR-lentivirus and transduced human Jurkat T or activated T cells from peripheral blood mononuclear cells (PBMCs) to produce CAR-T cells and tested for their quality attributes in vitro and in vivo. Serum enzymes including body weight from non-tumour bearing mice were tested for assessing general toxicity of CAR-T cells. RESULTS The binding of 14-1 clone is to IL-13Rα2Fc-chimeric protein is ∼5 times higher than our previous clone 4-1. The 14-1-CAR-T cells grew exponentially in the presence of cytokines and maintained phenotype and biological attributes such as cell viability, potency, migration and T cell activation. Clone 14-1 migrated to IL-13Rα2Fc and cell free supernatants only from IL-13Rα2+ve confluent glioma tumour cells in a chemotaxis assay. scFv-IL-13Rα2-CAR-T cells specifically killed IL-13Rα2+ve but not IL-13Rα2-ve tumour cells in vitro and selectively caused significant release of IFN-γ only from IL-13Rα2+ve co-cultures. These CAR-T cells regressed IL-13Rα2+ve glioma xenografts in vivo without any general toxicity. In contrast, the IL-13Rα2 gene knocked-down U251 and U87 xenografts failed to respond to the CAR-T therapy. CONCLUSION Taken together, we conclude that the novel scFv-IL-13Rα2 CAR-T cell therapy may offer an effective therapeutic option after designing a careful pre-clinical and clinical study.
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Affiliation(s)
- Pamela Leland
- Tumor Vaccine and Biotechnology BranchDivision of Cell Therapy IISilver SpringMarylandUSA
| | - Heba Degheidy
- Cellular and Tissue Therapy Branch, Office of Cellular Therapy & Human Tissues, Office of Therapeutic ProductsCenter for Biologics Evaluation and ResearchU.S. Food and Drug Administration, White OakSilver SpringMarylandUSA
| | - Ashley Lea
- Tumor Vaccine and Biotechnology BranchDivision of Cell Therapy IISilver SpringMarylandUSA
| | - Steven R. Bauer
- Cellular and Tissue Therapy Branch, Office of Cellular Therapy & Human Tissues, Office of Therapeutic ProductsCenter for Biologics Evaluation and ResearchU.S. Food and Drug Administration, White OakSilver SpringMarylandUSA
- Wake Forest Institute for Regenerative MedicineWinston‐SalemNorth CarolinaUSA
| | - Raj K. Puri
- Tumor Vaccine and Biotechnology BranchDivision of Cell Therapy IISilver SpringMarylandUSA
- Iovance Biotherapeutics, Inc.FrederickMarylandUSA
| | - Bharat H. Joshi
- Tumor Vaccine and Biotechnology BranchDivision of Cell Therapy IISilver SpringMarylandUSA
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Sturniolo I, Váróczy C, Regdon Z, Mázló A, Muzsai S, Bácsi A, Intili G, Hegedűs C, Boothby MR, Holechek J, Ferraris D, Schüler H, Virág L. PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype. Int J Mol Sci 2024; 25:3601. [PMID: 38612413 PMCID: PMC11011797 DOI: 10.3390/ijms25073601] [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: 02/15/2024] [Revised: 03/19/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
Cancers reprogram macrophages (MΦs) to a tumor-growth-promoting TAM (tumor-associated MΦ) phenotype that is similar to the anti-inflammatory M2 phenotype. Poly(ADP-ribose) polymerase (PARP) enzymes regulate various aspects of MΦ biology, but their role in the development of TAM phenotype has not yet been investigated. Here, we show that the multispectral PARP inhibitor (PARPi) PJ34 and the PARP14 specific inhibitor MCD113 suppress the expression of M2 marker genes in IL-4-polarized primary murine MΦs, in THP-1 monocytic human MΦs, and in primary human monocyte-derived MΦs. MΦs isolated from PARP14 knockout mice showed a limited ability to differentiate to M2 cells. In a murine model of TAM polarization (4T1 breast carcinoma cell supernatant transfer to primary MΦs) and in a human TAM model (spheroids formed from JIMT-1 breast carcinoma cells and THP-1-MΦs), both PARPis and the PARP14 KO phenotype caused weaker TAM polarization. Increased JIMT-1 cell apoptosis in co-culture spheroids treated with PARPis suggested reduced functional TAM reprogramming. Protein profiling arrays identified lipocalin-2, macrophage migration inhibitory factor, and plasminogen activator inhibitor-1 as potential (ADP-ribosyl)ation-dependent mediators of TAM differentiation. Our data suggest that PARP14 inhibition might be a viable anticancer strategy with a potential to boost anticancer immune responses by reprogramming TAMs.
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Affiliation(s)
- Isotta Sturniolo
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (C.V.); (Z.R.); (C.H.)
- Doctoral School of Molecular Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Csongor Váróczy
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (C.V.); (Z.R.); (C.H.)
- National Academy of Scientist Education, 4032 Debrecen, Hungary
| | - Zsolt Regdon
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (C.V.); (Z.R.); (C.H.)
| | - Anett Mázló
- Department of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.M.); (S.M.); (A.B.)
| | - Szabolcs Muzsai
- Department of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.M.); (S.M.); (A.B.)
- Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, University of Debrecen, 4032 Debrecen, Hungary
| | - Attila Bácsi
- Department of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.M.); (S.M.); (A.B.)
- HUN-REN-DE Allergology Research Group, 4032 Debrecen, Hungary
| | - Giorgia Intili
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy;
| | - Csaba Hegedűs
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (C.V.); (Z.R.); (C.H.)
| | - Mark R. Boothby
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN 37235, USA;
| | | | - Dana Ferraris
- Department of Chemistry, McDaniel College, Westminster, MD 21157, USA;
| | - Herwig Schüler
- Center for Molecular Protein Science, Department of Chemistry, Lund University, 22100 Lund, Sweden;
| | - László Virág
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (C.V.); (Z.R.); (C.H.)
- HUN-REN-DE Cell Biology and Signaling Research Group, 4032 Debrecen, Hungary
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11
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Triantafillidis JK, Konstadoulakis MM, Papalois AE. Immunotherapy of gastric cancer: Present status and future perspectives. World J Gastroenterol 2024; 30:779-793. [PMID: 38516237 PMCID: PMC10950642 DOI: 10.3748/wjg.v30.i8.779] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 12/14/2023] [Accepted: 01/29/2024] [Indexed: 02/26/2024] Open
Abstract
In this editorial, we comment on the article entitled "Advances and key focus areas in gastric cancer immunotherapy: A comprehensive scientometric and clinical trial review (1999-2023)," which was published in the recent issue of the World Journal of Gastroenterology. We focused on the results of the authors' bibliometric analysis concerning gastric cancer immunotherapy, which they analyzed in depth by compiling the relevant publications of the last 20 years. Before that, we briefly describe the most recent data concerning the epidemiological parameters of gastric cancer (GC) in different countries, attempting to give an interpretation based on the etiological factors involved in the etiopathogenesis of the neoplasm. We then briefly discuss the conservative treatment (chemotherapy) of the various forms of this malignant neoplasm. We describe the treatment of resectable tumors, locally advanced neoplasms, and unresectable (advanced) cases. Special attention is given to modern therapeutic approaches with emphasis on immunotherapy, which seems to be the future of GC treatment, especially in combination with chemotherapy. There is also a thorough analysis of the results of the study under review in terms of the number of scientific publications, the countries in which the studies were conducted, the authors, and the scientific centers of origin, as well as the clinical studies in progress. Finally, an attempt is made to draw some con-clusions and to point out possible future directions.
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Affiliation(s)
- John K Triantafillidis
- Inflammatory Bowel Disease Unit, “Metropolitan General” Hospital, Holargos 15562, Attica, Greece. Hellenic Society for Gastrointestinal Oncology, 354 Iera Odos, Chaidari 12461, Attica, Greece
| | - Manousos M Konstadoulakis
- Second Department of Surgery, University of Athens School of Medicine, Aretaieion Hospital, Athens 11528, Attica, Greece
| | - Apostolos E Papalois
- Unit of Surgical Research and Training, Second Department of Surgery, University of Athens, School of Medicine, Aretaieion Hospital, Athens 11528, Attica, Greece
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Zhang B, Yang M, Zhang W, Liu N, Wang D, Jing L, Xu N, Yang N, Ren T. Chimeric antigen receptor-based natural killer cell immunotherapy in cancer: from bench to bedside. Cell Death Dis 2024; 15:50. [PMID: 38221520 PMCID: PMC10788349 DOI: 10.1038/s41419-024-06438-7] [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: 09/11/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 01/16/2024]
Abstract
Immunotherapy has rapidly evolved in the past decades in the battle against cancer. Chimeric antigen receptor (CAR)-engineered T cells have demonstrated significant success in certain hematologic malignancies, although they still face certain limitations, including high costs and toxic effects. Natural killer cells (NK cells), as a vital component of the immune system, serve as the "first responders" in the context of cancer development. In this literature review, we provide an updated understanding of NK cell development, functions, and their applications in disease therapy. Furthermore, we explore the rationale for utilizing engineered NK cell therapies, such as CAR-NK cells, and discuss the differences between CAR-T and CAR-NK cells. We also provide insights into the key elements and strategies involved in CAR design for engineered NK cells. In addition, we highlight the challenges currently encountered and discuss the future directions in NK cell research and utilization, including pre-clinical investigations and ongoing clinical trials. Based on the outstanding antitumor potential of NK cells, it is highly likely that they will lead to groundbreaking advancements in cancer treatment in the future.
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Affiliation(s)
- Beibei Zhang
- Institute of Biomedical Research, Yunnan University, Kunming, 650500, China.
| | - Mengzhe Yang
- Graduate School of Capital Medical University, Beijing, 100069, China
| | - Weiming Zhang
- Department of Oncology, Wuming Hospital of Guangxi Medical University, Nanning, 530199, China
| | - Ning Liu
- Department of Hematology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China
| | - Daogang Wang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530000, China
| | - Liangfang Jing
- Department of Neonatology, Women and Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530005, China
| | - Ning Xu
- Department of Clinical Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, 530000, China
| | - Na Yang
- Department of Ultrasound, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650101, China.
| | - Tao Ren
- Department of Oncology, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, 530000, China.
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Wang C, Wang J, Che S, Zhao H. CAR-T cell therapy for hematological malignancies: History, status and promise. Heliyon 2023; 9:e21776. [PMID: 38027932 PMCID: PMC10658259 DOI: 10.1016/j.heliyon.2023.e21776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 10/19/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
For many years, the methods of cancer treatment are usually surgery, chemotherapy and radiation therapy. Although these methods help to improve the condition, most tumors still have a poor prognosis. In recent years, immunotherapy has great potential in tumor treatment. Chimeric antigen receptor T-cell immunotherapy (CAR-T) uses the patient's own T cells to express chimeric antigen receptors. Chimeric antigen receptor (CAR) recognizes tumor-associated antigens and kills tumor cells. CAR-T has achieved good results in the treatment of hematological tumors. In 2017, the FDA approved the first CAR-T for the treatment of B-cell acute lymphoblastic leukemia (ALL). In October of the same year, the FDA approved CAR-T to treat B-cell lymphoma. In order to improve and enhance the therapeutic effect, CAR-T has become a research focus in recent years. The structure of CAR, the targets of CAR-T treatment, adverse reactions and improvement measures during the treatment process are summarized. This review is an attempt to highlight recent and possibly forgotten findings of advances in chimeric antigen receptor T cell for treatment of hematological tumors.
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Affiliation(s)
- Chao Wang
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong, 266005, China
| | - Jianpeng Wang
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong, 266005, China
| | - Shusheng Che
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong, 266005, China
| | - Hai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong, 266005, China
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Sayadmanesh A, Azadbakht M, Yari K, Abedelahi A, Shafaei H, Shanehbandi D, Baradaran B, Basiri M. Characterization of CAR T Cells Manufactured Using Genetically Engineered Artificial Antigen Presenting Cells. CELL JOURNAL 2023; 25:674-687. [PMID: 37865876 PMCID: PMC10591261 DOI: 10.22074/cellj.2023.2001712.1304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/22/2023] [Accepted: 07/01/2023] [Indexed: 10/23/2023]
Abstract
OBJECTIVE Chimeric antigen receptor (CAR) T cell therapy has recently emerged as a promising approach for the treatment of different types of cancer. Improving CAR T cell manufacturing in terms of costs and product quality is an important concern for expanding the accessibility of this therapy. One proposed strategy for improving T cell expansion is to use genetically engineered artificial antigen presenting cells (aAPC) expressing a membrane-bound anti-CD3 for T cell activation. The aim of this study was to characterize CAR T cells generated using this aAPC-mediated approach in terms of expansion efficiency, immunophenotype, and cytotoxicity. MATERIALS AND METHODS In this experimental study, we generated an aAPC line by engineering K562 cells to express a membrane-bound anti-CD3 (mOKT3). T cell activation was performed by co-culturing PBMCs with either mitomycin C-treated aAPCs or surface-immobilized anti-CD3 and anti-CD28 antibodies. Untransduced and CD19-CARtransduced T cells were characterized in terms of expansion, activation markers, interferon gamma (IFN-γ) secretion, CD4/CD8 ratio, memory phenotype, and exhaustion markers. Cytotoxicity of CD19-CAR T cells generated by aAPCs and antibodies were also investigated using a bioluminescence-based co-culture assay. RESULTS Our findings showed that the engineered aAPC line has the potential to expand CAR T cells similar to that using the antibody-based method. Although activation with aAPCs leads to a higher ratio of CD8+ and effector memory T cells in the final product, we did not observe a significant difference in IFN-γ secretion, cytotoxic activity or exhaustion between CAR T cells generated with aAPC or antibodies. CONCLUSION Our results show that despite the differences in the immunophenotypes of aAPC and antibody-based CAR T cells, both methods can be used to manufacture potent CAR T cells. These findings are instrumental for the improvement of the CAR T cell manufacturing process and future applications of aAPC-mediated expansion of CAR T cells.
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Affiliation(s)
- Ali Sayadmanesh
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mohamad Azadbakht
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Kheirollah Yari
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Abedelahi
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajar Shafaei
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohsen Basiri
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Leland P, Kumar D, Nimmagadda S, Bauer SR, Puri RK, Joshi BH. Characterization of chimeric antigen receptor modified T cells expressing scFv-IL-13Rα2 after radiolabeling with 89Zirconium oxine for PET imaging. J Transl Med 2023; 21:367. [PMID: 37286997 PMCID: PMC10246418 DOI: 10.1186/s12967-023-04142-2] [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: 11/07/2022] [Accepted: 04/19/2023] [Indexed: 06/09/2023] Open
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T cell therapy is an exciting cell-based cancer immunotherapy. Unfortunately, CAR-T cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and neurotoxicity. The mechanism of these serious adverse events (SAEs) and how homing, distribution and retention of CAR-T cells contribute to toxicities is not fully understood. Enabling in vitro methods to allow meaningful, sensitive in vivo biodistribution studies is needed to better understand CAR-T cell disposition and its relationship to both effectiveness and safety of these products. METHODS To determine if radiolabelling of CAR-T cells could support positron emission tomography (PET)-based biodistribution studies, we labeled IL-13Rα2 targeting scFv-IL-13Rα2-CAR-T cells (CAR-T cells) with 89Zirconium-oxine (89Zr-oxine) and characterized and compared their product attributes with non-labeled CAR-T cells. The 89Zr-oxine labeling conditions were optimized for incubation time, temperature, and use of serum for labeling. In addition, T cell subtype characterization and product attributes of radiolabeled CAR-T cells were studied to assess their overall quality including cell viability, proliferation, phenotype markers of T-cell activation and exhaustion, cytolytic activity and release of interferon-γ upon co-culture with IL-13Rα2 expressing glioma cells. RESULTS We observed that radiolabeling of CAR-T cells with 89Zr-oxine is quick, efficient, and radioactivity is retained in the cells for at least 8 days with minimal loss. Also, viability of radiolabeled CAR-T cells and subtypes such as CD4 + , CD8 + and scFV-IL-13Rα2 transgene positive T cell population were characterized and found similar to that of unlabeled cells as determined by TUNEL assay, caspase 3/7 enzyme and granzyme B activity assay. Moreover, there were no significant changes in T cell activation (CD24, CD44, CD69 and IFN-γ) or T cell exhaustion (PD-1, LAG-3 and TIM3) markers expression between radiolabeled and unlabeled CAR-T cells. In chemotaxis assays, migratory capability of radiolabeled CAR-T cells to IL-13Rα2Fc was similar to that of non-labeled cells. CONCLUSIONS Importantly, radiolabeling has minimal impact on biological product attributes including potency of CAR-T cells towards IL-13Rα2 positive tumor cells but not IL-13Rα2 negative cells as measured by cytolytic activity and release of IFN-γ. Thus, IL-13Rα2 targeting CAR-T cells radiolabeled with 89Zr-oxine retain critical product attributes and suggest 89Zr-oxine radiolabeling of CAR-T cells may facilitate biodistribution and tissue trafficking studies in vivo using PET.
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Affiliation(s)
- Pamela Leland
- Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Office of Tissues and Advance Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
| | - Dhiraj Kumar
- Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sridhar Nimmagadda
- Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Steven R Bauer
- Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Office of Tissues and Advance Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
- Wake Forest Institute of Regenerative Medicine, Winston Salem, North Caroline, USA
| | - Raj K Puri
- Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Office of Tissues and Advance Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
- Iovance Biotherapeutics, San Carlos, CA, USA
| | - Bharat H Joshi
- Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Office of Tissues and Advance Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
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16
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Li YR, Dunn ZS, Yu Y, Li M, Wang P, Yang L. Advancing cell-based cancer immunotherapy through stem cell engineering. Cell Stem Cell 2023; 30:592-610. [PMID: 36948187 PMCID: PMC10164150 DOI: 10.1016/j.stem.2023.02.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 01/04/2023] [Accepted: 02/22/2023] [Indexed: 03/24/2023]
Abstract
Advances in cell-based therapy, particularly CAR-T cell therapy, have transformed the treatment of hematological malignancies. Although an important step forward for the field, autologous CAR-T therapies are hindered by high costs, manufacturing challenges, and limited efficacy against solid tumors. With ongoing progress in gene editing and culture techniques, engineered stem cells and their application in cell therapy are poised to address some of these challenges. Here, we review stem cell-based immunotherapy approaches, stem cell sources, gene engineering and manufacturing strategies, therapeutic platforms, and clinical trials, as well as challenges and future directions for the field.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zachary Spencer Dunn
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA
| | - Yanqi Yu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Miao Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Pin Wang
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
| | - Lili Yang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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Stuckey R, Luzardo Henríquez H, de la Nuez Melian H, Rivero Vera JC, Bilbao-Sieyro C, Gómez-Casares MT. Integration of molecular testing for the personalized management of patients with diffuse large B-cell lymphoma and follicular lymphoma. World J Clin Oncol 2023; 14:160-170. [PMID: 37124135 PMCID: PMC10134203 DOI: 10.5306/wjco.v14.i4.160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/24/2023] [Accepted: 04/04/2023] [Indexed: 04/21/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common forms of aggressive and indolent lymphoma, respectively. The majority of patients are cured by standard R-CHOP immunochemotherapy, but 30%–40% of DLBCL and 20% of FL patients relapse or are refractory (R/R). DLBCL and FL are phenotypically and genetically hereterogenous B-cell neoplasms. To date, the diagnosis of DLBCL and FL has been based on morphology, immunophenotyping and cytogenetics. However, next-generation sequencing (NGS) is widening our understanding of the genetic basis of the B-cell lymphomas. In this review we will discuss how integrating the NGS-based characterization of somatic gene mutations with diagnostic or prognostic value in DLBCL and FL could help refine B-cell lymphoma classification as part of a multidisciplinary pathology work-up. We will also discuss how molecular testing can identify candidates for clinical trials with targeted therapies and help predict therapeutic outcome to currently available treatments, including chimeric antigen receptor T-cell, as well as explore the application of circulating cell-free DNA, a non-invasive method for patient monitoring. We conclude that molecular analyses can drive improvements in patient outcomes due to an increased understanding of the different pathogenic pathways affected by each DLBCL subtype and indolent FL vs R/R FL.
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Affiliation(s)
- Ruth Stuckey
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas 35019, Spain
| | - Hugo Luzardo Henríquez
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas 35019, Spain
| | | | - José Carlos Rivero Vera
- Department of Anatomical Pathology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas 35019, Spain
| | - Cristina Bilbao-Sieyro
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria 35019, Las Palmas de Gran Canaria, Spain
- Department of Morphology, Universitario de Las Palmas de Gran Canaria, Las Palmas 35001, Spain
| | - María Teresa Gómez-Casares
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria 35019, Las Palmas de Gran Canaria, Spain
- Medical Science, Universitario de Las Palmas de Gran Canaria, Las Palmas 35001, Spain
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18
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Sharma S, Woods M, Mehta NU, Sauer T, Parikh KS, Schmuck-Henneresse M, Zhang H, Mehta B, Brenner MK, Heslop HE, Rooney CM. Naive T cells inhibit the outgrowth of intractable antigen-activated memory T cells: implications for T-cell immunotherapy. J Immunother Cancer 2023; 11:e006267. [PMID: 37072346 PMCID: PMC10124261 DOI: 10.1136/jitc-2022-006267] [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] [Accepted: 03/23/2023] [Indexed: 04/20/2023] Open
Abstract
BACKGROUND The wider application of T cells targeting viral tumor-antigens via their native receptors is hampered by the failure to expand potent tumor-specific T cells from patients. Here, we examine reasons for and solutions to this failure, taking as our model the preparation of Epstein-Barr virus (EBV)-specific T cells (EBVSTs) for the treatment of EBV-positive lymphoma. EBVSTs could not be manufactured from almost one-third of patients, either because they failed to expand, or they expanded, but lacked EBV specificity. We identified an underlying cause of this problem and established a clinically feasible approach to overcome it. METHODS CD45RO+CD45RA- memory compartment residing antigen-specific T cells were enriched by depleting CD45RA positive (+) peripheral blood mononuclear cells (PBMCs) that include naïve T cells, among other subsets, prior to EBV antigen stimulation. We then compared the phenotype, specificity, function and T-cell receptor (TCR) Vβ repertoire of EBVSTs expanded from unfractionated whole (W)-PBMCs and CD45RA-depleted (RAD)-PBMCs on day 16. To identify the CD45RA component that inhibited EBVST outgrowth, isolated CD45RA+ subsets were added back to RAD-PBMCs followed by expansion and characterization. The in vivo potency of W-EBVSTs and RAD-EBVSTs was compared in a murine xenograft model of autologous EBV+ lymphoma. RESULTS Depletion of CD45RA+ PBMCs before antigen stimulation increased EBVST expansion, antigen-specificity and potency in vitro and in vivo. TCR sequencing revealed a selective outgrowth in RAD-EBVSTs of clonotypes that expanded poorly in W-EBVSTs. Inhibition of antigen-stimulated T cells by CD45RA+ PBMCs could be reproduced only by the naïve T-cell fraction, while CD45RA+ regulatory T cells, natural killer cells, stem cell memory and effector memory subsets lacked inhibitory activity. Crucially, CD45RA depletion of PBMCs from patients with lymphoma enabled the outgrowth of EBVSTs that failed to expand from W-PBMCs. This enhanced specificity extended to T cells specific for other viruses. CONCLUSION Our findings suggest that naïve T cells inhibit the outgrowth of antigen-stimulated memory T cells, highlighting the profound effects of intra-T-cell subset interactions. Having overcome our inability to generate EBVSTs from many patients with lymphoma, we have introduced CD45RA depletion into three clinical trials: NCT01555892 and NCT04288726 using autologous and allogeneic EBVSTs to treat lymphoma and NCT04013802 using multivirus-specific T cells to treat viral infections after hematopoietic stem cell transplantation.
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Affiliation(s)
- Sandhya Sharma
- Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
| | - Mae Woods
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
| | - Naren U Mehta
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
| | - Tim Sauer
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
| | - Kathan S Parikh
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
| | - Michael Schmuck-Henneresse
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, Berlin, Germany
| | - Huimin Zhang
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
| | - Birju Mehta
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
| | - Malcolm K Brenner
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA
| | - Helen E Heslop
- Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA
| | - Cliona M Rooney
- Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
- Department of Pathology-Immunology, Baylor College of Medicine, Houston, Texas, USA
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Cytokine Release Syndrome in the Pediatric Population and Implications for Intensive Care Management. Crit Care Clin 2023; 39:277-285. [PMID: 36898773 DOI: 10.1016/j.ccc.2022.09.004] [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: 11/19/2022]
Abstract
Cytokine release syndrome represents a spectrum of disease varying from fever alone to multiorgan system failure. Most commonly seen following treatment with chimeric antigen receptor T cell therapy, it is increasingly being described with other immunotherapies as well as following hematopoietic stem cell transplant. As its symptoms are nonspecific, awareness is key to timely diagnosis and initiation of treatment. Given the high risk of cardiopulmonary involvement, critical care providers must be familiar with the cause, symptoms, and therapeutic options. Current treatment modalities focus on immunosuppression and targeted cytokine therapy.
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A novel biocompatible polymer derived from D-mannitol used as a vector in the field of genetic engineering of eukaryotic cells. Colloids Surf B Biointerfaces 2023; 224:113219. [PMID: 36848782 DOI: 10.1016/j.colsurfb.2023.113219] [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: 11/15/2022] [Revised: 02/15/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023]
Abstract
The design and preparation of new vectors to transport genetic material and increase the transfection efficiency continue being an important research line. Here, a novel biocompatible sugar-based polymer derived from D-mannitol has been synthesized to be used as a gene material nanocarrier in human (gene transfection) and microalga cells (transformation process). Its low toxicity allows its use in processes with both medical and industrial applications. A multidisciplinary study about the formation of polymer/p-DNA polyplexes has been carried out using techniques such as gel electrophoresis, zeta potential, dynamic light scattering, atomic force microscopy, and circular dichroism spectroscopy. The nucleic acids used were the eukaryotic expression plasmid pEGFP-C1 and the microalgal expression plasmid Phyco69, which showed different behaviors. The importance of DNA supercoiling in both transfection and transformation processes was demonstrated. Better results were obtained in microalga cells nuclear transformation than in human cells gene transfection. This was related to the plasmid's conformational changes, in particular to their superhelical structure. It is noteworthy that the same nanocarrier has been used with eukaryotic cells from both human and microalga.
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Leland P, Kumar D, Nimaggada S, Bauer SR, Puri RK, Joshi BH. Characterization of Chimeric Antigen Receptor Modified T Cells Expressing scFv-IL-13Rα2 after Radiolabeling with 89Zirconium Oxine for PET Imaging. RESEARCH SQUARE 2023:rs.3.rs-2242559. [PMID: 36711796 PMCID: PMC9882610 DOI: 10.21203/rs.3.rs-2242559/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Background Chimeric antigen receptor (CAR) T cell therapy is an exciting cell-based cancer immunotherapy. Unfortunately, CAR-T cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and neurotoxicity. The mechanism of these serious adverse events (SAEs) and how homing, distribution and retention of CAR-T cells contribute to toxicities is not fully understood. Methods To determine if radiolabelling of CAR-T cells could support positron emission tomography (PET)-based biodistribution studies, we labeled IL-13Rα2 targeting scFv-IL-13Rα2-CAR-T cells (CAR-T cells) with 89 Zirconium-oxine ( 89 Zr-oxine), and characterized and compared their product attributes with non-labeled CAR-T cells. The 89 Zr-oxine labeling conditions were optimized for incubation time, temperature, and use of serum for labeling. In addition, product attributes of radiolabeled CAR-T cells were studied to assess their overall quality including cell viability, proliferation, phenotype markers of T-cell activation and exhaustion, cytolytic activity and release of interferon-γ upon co-culture with IL-13Rα2 expressing glioma cells. Results We observed that radiolabeling of CAR-T cells with 89 Zr-oxine is quick, efficient, and radioactivity is retained in the cells for at least 8 days with minimal loss. Also, viability of radiolabeled CAR-T cells was similar to that of unlabeled cells as determined by TUNEL assay and caspase 3/7 enzyme activity assay. Moreover, there were no significant changes in T cell activation (CD24, CD44, CD69 and IFN-γ) or T cell exhaustion(PD-1, LAG-3 and TIM3) markers expression between radiolabeled and unlabeled CAR-T cells. In chemotaxis assays, migratory capability of radiolabeled CAR-T cells to IL-13Rα2Fc was similar to that of non-labeled cells. Conclusions Importantly, radiolabeling has minimal impact on biological product attributes including potency of CAR-T cells towards IL-13Rα2 positive tumor cells but not IL-13Rα2 negative cells as measured by cytolytic activity and release of IFN-γ. Thus, IL-13Rα2 targeting CAR-T cells radiolabeled with 89 Zr-oxine retain critical product attributes and suggest 89 Zr-oxine radiolabeling of CAR-T cells may facilitate biodistribution and tissue trafficking studies in vivo using PET.
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Affiliation(s)
| | - Dhiraj Kumar
- Johns Hopkins Medicine School of Medicine: Johns Hopkins University School of Medicine
| | | | | | - Raj K Puri
- Center for Biologics Evaluation and Research
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Lin L, Liu X, Yu H, Deng H, Peng K, Chen J, Zhang C, Jiang T, Liu X. Inhibitory effect and related mechanism of decitabine combined with gemcitabine on proliferation of NK/T cell lymphoma cells. Front Pharmacol 2023; 14:1134895. [PMID: 36937854 PMCID: PMC10014839 DOI: 10.3389/fphar.2023.1134895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 02/14/2023] [Indexed: 03/05/2023] Open
Abstract
Background: EBV-associated lymphoma is a neoplasm with a poor prognosis, highly aggressive, and progressive rapidly. There is no standard clinical treatment protocol. Decitabine and gemcitabine are known to have anticancer properties against cells of various cancer, respectively. However, the effect of the combination medication on NK/T cell lymphoma cells and potential mechanisms have not been thoroughly investigated. Methods: Human NK/T cell lymphoma cells NK92MI were treated with decitabine and gemcitabine alone or in combination. Experiments, including the Cell Counting Kit-8 and flow cytometry, were performed to investigate how the combination of decitabine and gemcitabine affects the biological behavior of NK92MI cells in vitro. mRNA sequencing, RT-PCR, and western blotting were used to detect changes in the related signal pathway, mRNA, and protein expressions. Results: Decitabine and gemcitabine significantly inhibited the viability and proliferation of NK92MI cells in a dose-dependent manner. The combination index was less than 1 after treating with two drugs, which was a significant synergistic effect. The decitabine concentration with the best synergistic effect was 4.046 µM, and the gemcitabine concentration was 0.005 µM. Flow cytometry showed that combining two drugs could significantly promote apoptosis and arrest the cell cycle at the S phase. In the combined DAC and GEM group, caspase3 protein levels were higher than in either group alone or the control group. The transcriptome sequence, KEGG, and PPI analysis showed that the differential genes after combined treatment were mainly enriched in signal pathways related to cell proliferation, adhesion, and migration compared with using alone and control groups. Based on the sequencing results, we further investigated the role of DAC and GEM in ferroptosis-related signaling molecules using RT-PCR and Western blot techniques. RT-PCR and western blotting showed that the expression levels of HMOX1 and EBV cleavage gene BRLF1 were higher in the group with combined DAC and GEM than in the group alone and the control group, while the protein and mRNA expression levels of SLC7A11 were lower than the others. In addition, the GPX4 protein expression level in the combination group was lower than in the drug-alone and control groups. In addition, the combination treatment increased the ROS level of NK92MI cells. Conclusion: Our current findings suggested that decitabine had an inhibitory effect on the proliferation of NK92MI cells when co-treated with gemcitabine. This combination may increase the expression of ferroptosis-related signaling molecules, thus inhibiting the proliferation of NK92MI cells. It also promoted apoptosis in NK/T cell lymphoma. For patients with NK/T cell lymphoma, this novel combination may provide clinical benefits.
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Affiliation(s)
- Lanke Lin
- College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiangqin Liu
- Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Hui Yu
- Department of Laboratory Medicine, The People’s Hospital of Leshan, Leshan, China
| | - Huan Deng
- College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kun Peng
- Health Management Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jiang Chen
- The Department of Ophthalmology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Chunle Zhang
- Division of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
- *Correspondence: Xiaoqi Liu, ; Tao Jiang, ; Chunle Zhang,
| | - Tao Jiang
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China
- *Correspondence: Xiaoqi Liu, ; Tao Jiang, ; Chunle Zhang,
| | - Xiaoqi Liu
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital,, Chengdu, Sichuan, China
- *Correspondence: Xiaoqi Liu, ; Tao Jiang, ; Chunle Zhang,
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Divergent paths: management of early relapsed follicular lymphoma. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2022; 2022:666-675. [PMID: 36485106 PMCID: PMC9820493 DOI: 10.1182/hematology.2022000360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the United States and Western Europe. Overall outcomes for patients with FL have continued to improve over the last several decades-most notably, with the addition of the CD20 monoclonal antibody rituximab to the treatment armamentarium. More recently, we have seen advances in the management of patients with relapsed/refractory FL with the approval of several new treatments including lenalidomide, axicabtagene ciloleucel, copanlisib, umbralisib, and tazemetostat. Unfortunately, there remains a group of patients for which treatment outcomes, especially overall survival (OS), are suboptimal. This group has been identified as patients who relapse within 24 months (POD24) of completion of chemoimmunotherapy (CIT). Data indicate that patients who relapse within this window have a 5-year OS of around 50%, compared to 80% for those who remain in remission beyond 24 months. POD24 patients have been included and evaluated in the studies of the novel agents mentioned. While not specifically designed to treat this high-risk group, early data suggest that outcomes are not significantly impacted by this designation, unlike CIT. While to date the optimal management of POD24 patients has not been elucidated, the future appears bright with the continued use of the approved agents and several others in clinical development.
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Chimeric antigen receptor clustering via cysteines enhances T-cell efficacy against tumor. Cancer Immunol Immunother 2022; 71:2801-2814. [DOI: 10.1007/s00262-022-03195-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/24/2022] [Indexed: 10/18/2022]
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25
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Wang CY, Ting Cheung SP, Sugimura R. Combating challenges in CAR-T cells with engineering immunology. Front Cell Dev Biol 2022; 10:969020. [PMID: 36299480 PMCID: PMC9589253 DOI: 10.3389/fcell.2022.969020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 09/14/2022] [Indexed: 03/27/2024] Open
Abstract
Chimeric antigen receptors (CAR) T cells (CAR-T) mark a significant step towards producing safe and effective personal anticancer treatments. CAR-T strategies engineers the T cells from the patients to allow specific binding to a tumour-specific antigen. CAR-Ts are a second-wave offensive strategy to clear out remaining chemotherapy-resistant tumour cells. Though showing practical antitumor abilities in multiple haematological malignancies and solid tumour cancers, the issues of antigen escape, tumour infiltration/penetration, and toxicity side effects limit the usage of prolonged CAR-T therapies. However, engineering immunology has exploited human stem cell-based CAR-T therapies and the development of CAR-M (macrophage) therapies to combat the disadvantages of conventional CAR-T therapies. In this review, we will highlight the challenges of CAR-T therapies and combat them with engineering immunology for cancer immunotherapy.
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Affiliation(s)
| | | | - Ryohichi Sugimura
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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26
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He X, Zeng XX. Immunotherapy and CRISPR Cas Systems: Potential Cure of COVID-19? Drug Des Devel Ther 2022; 16:951-972. [PMID: 35386853 PMCID: PMC8979261 DOI: 10.2147/dddt.s347297] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 03/16/2022] [Indexed: 12/15/2022] Open
Abstract
The COVID-19 has plunged the world into a pandemic that affected millions. The continually emerging new variants of concern raise the question as to whether the existing vaccines will continue to provide sufficient protection for individuals from SARS-CoV-2 during natural infection. This narrative review aims to briefly outline various immunotherapeutic options and discuss the potential of clustered regularly interspaced short palindromic repeat (CRISPR Cas system technology against COVID-19 treatment as specific cure. As the development of vaccine, convalescent plasma, neutralizing antibodies are based on the understanding of human immune responses against SARS-CoV-2, boosting human body immune responses in case of SARS-CoV-2 infection, immunotherapeutics seem feasible as specific cure against COVID-19 if the present challenges are overcome. In cell based therapeutics, apart from the high costs, risks and side effects, there are technical problems such as the production of sufficient potent immune cells and antibodies under limited time to treat the COVID-19 patients in mild conditions prior to progression into a more severe case. The CRISPR Cas technology could be utilized to refine the specificity and safety of CAR-T cells, CAR-NK cells and neutralizing antibodies against SARS-CoV-2 during various stages of the COVID-19 disease progression in infected individuals. Moreover, CRISPR Cas technology are proposed in hypotheses to degrade the viral RNA in order to terminate the infection caused by SARS-CoV-2. Thus personalized cocktails of immunotherapeutics and CRISPR Cas systems against COVID-19 as a strategy might prevent further disease progression and circumvent immunity escape.
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Affiliation(s)
- Xuesong He
- Department of Cardiology, Changzhou Jintan First People’s Hospital, Changzhou City, Jiangsu Province, 213200, People’s Republic of China
| | - Xiao Xue Zeng
- Department of Health Management, Centre of General Practice, The Seventh Affiliated Hospital, Southern Medical University, Foshan City, Guangdong Province, 528000, People’s Republic of China
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27
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Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion. Nat Rev Clin Oncol 2022; 19:342-355. [PMID: 35318469 DOI: 10.1038/s41571-022-00607-3] [Citation(s) in RCA: 158] [Impact Index Per Article: 52.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2022] [Indexed: 12/14/2022]
Abstract
Chimeric antigen receptor (CAR) T cells have emerged as a potent therapeutic approach for patients with certain haematological cancers, with multiple CAR T cell products currently approved by the FDA for those with relapsed and/or refractory B cell malignancies. However, in order to derive the desired level of effectiveness, patients need to successfully receive the CAR T cell infusion in a timely fashion. This process entails apheresis of the patient's T cells, followed by CAR T cell manufacture. While awaiting infusion at an authorized treatment centre, patients may receive interim disease-directed therapy. Most patients will also receive a course of pre-CAR T cell lymphodepletion, which has emerged as an important factor in enabling durable responses. The time between apheresis and CAR T cell infusion is often not a simple journey, with each milestone being a critical step that can have important downstream consequences for the ability to receive the infusion and the strength of clinical responses. In this Review, we provide a summary of the many considerations for preparing patients with B cell non-Hodgkin lymphoma or acute lymphoblastic leukaemia for CAR T cell therapy, and outline current limitations and areas for future research.
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28
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Xin T, Cheng L, Zhou C, Zhao Y, Hu Z, Wu X. In-Vivo Induced CAR-T Cell for the Potential Breakthrough to Overcome the Barriers of Current CAR-T Cell Therapy. Front Oncol 2022; 12:809754. [PMID: 35223491 PMCID: PMC8866962 DOI: 10.3389/fonc.2022.809754] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022] Open
Abstract
Chimeric antigen receptor T cell (CAR-T cell) therapy has shown impressive success in the treatment of hematological malignancies, but the systemic toxicity and complex manufacturing process of current autologous CAR-T cell therapy hinder its broader applications. Universal CAR-T cells have been developed to simplify the production process through isolation and editing of allogeneic T cells from healthy persons, but the allogeneic CAR-T cells have recently encountered safety concerns, and clinical trials have been halted by the FDA. Thus, there is an urgent need to seek new ways to overcome the barriers of current CAR-T cell therapy. In-vivo CAR-T cells induced by nanocarriers loaded with CAR-genes and gene-editing tools have shown efficiency for regressing leukemia and reducing systemic toxicity in a mouse model. The in-situ programming of autologous T-cells avoids the safety concerns of allogeneic T cells, and the manufacture of nanocarriers can be easily standardized. Therefore, the in-vivo induced CAR-T cells can potentially overcome the abovementioned limitations of current CAR-T cell therapy. Here, we provide a review on CAR structures, gene-editing tools, and gene delivery techniques applied in immunotherapy to help design and develop new in-vivo induced CAR-T cells.
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Affiliation(s)
- Tianqing Xin
- Department of Pediatrics, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Li Cheng
- Department of Pediatrics, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Chuchao Zhou
- Department of Pediatrics, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yimeng Zhao
- Department of Pediatrics, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenhua Hu
- Department of Health and Nursing, Nanfang College of Sun Yat-sen University, Guangzhou, China
| | - Xiaoyan Wu
- Department of Pediatrics, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
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29
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Chen XH, Chen R, Shi MY, Tian RF, Zhang H, Xin ZQ, Chen ZN, Wang K. Chimeric antigen receptor T cells targeting CD147 for non-small cell lung cancer therapy. Transl Oncol 2022; 16:101309. [PMID: 34896852 PMCID: PMC8681039 DOI: 10.1016/j.tranon.2021.101309] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/23/2021] [Accepted: 12/06/2021] [Indexed: 12/25/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is a highly malignant tumor, with a significant mortality and morbidity. With the development of tumor immunotherapy, chimeric antigen receptor T cells (CART) gets increasingly attention and achieves prominent contributions in the treatment of hematologic malignancies. However, CART therapy for NSCLC proceeds slowly and further researches need to be investigated. In our study, we performed bioinformatics analysis to evaluate the significant role of CD147 in NSCLC. The expression level of CD147 was detected in human NSCLC cell lines and NSCLC tissues. Meanwhile, CD147-CART was constructed and identified. Cell cytotoxicity and cytokine secretion were performed to evaluate the efficacy of CD147-CART. We also constructed cell-derived xenograft (CDX) model and patient-derived xenograft (PDX) model, which was used to further investigate the safety and efficacy of CD147-CART in vivo. Our observations show that CD147 is a specific tumor antigen of NSCLC and plays an essential role in NSCLC progression, which can be used as a target for CART therapy in NSCLC. CD147-CART cells exhibit robust cytotoxicity and cytokine production in vitro, suggesting a strong anti-tumor activity against NSCLC tumor cells. Importantly, CD147-CART cells have strong anti-tumor activity against NSCLC cells in vivo in both CDX and PDX models and no adverse side effects. Our findings show that CD147-CART immunotherapy for NSCLC is safe and effective, which is an ideal and promising medical patch for treating NSCLC.
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Affiliation(s)
- Xiao-Hong Chen
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China
| | - Ruo Chen
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China
| | - Ming-Yan Shi
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China
| | - Ruo-Fei Tian
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China
| | - Hai Zhang
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China
| | - Zhi-Qian Xin
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China
| | - Zhi-Nan Chen
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
| | - Ke Wang
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
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Should CD19 CAR-T Cells for ALL be Followed by Allogeneic Stem Cell Transplant? Transplant Cell Ther 2022; 28:1-2. [DOI: 10.1016/j.jtct.2021.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Sheykhhasan M, Manoochehri H, Dama P. Use of CAR T-cell for acute lymphoblastic leukemia (ALL) treatment: a review study. Cancer Gene Ther 2022; 29:1080-1096. [PMID: 34987176 PMCID: PMC9395272 DOI: 10.1038/s41417-021-00418-1] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 11/18/2021] [Accepted: 12/13/2021] [Indexed: 02/08/2023]
Abstract
Acute lymphoblastic leukemia (ALL) is a cancer-specific lymphoid cell. Induction and consolidation chemotherapy alone or in combination with different therapeutic approaches remain the main treatment. Although complete or partial remission of the disease can be achieved, the risk of relapse or refractory leukemia is still high. More effective and safe therapy options are yet unmet needs. In recent years' new therapeutic approaches have been widely used. Hematopoietic Stem Cell Transplantation (HSCT) presents significant limitations and the outcome of the consolidation treatment is patient dependent. Side effects such as Graft versus Host Disease (GvHD) in allogeneic hematopoietic stem cell transplantation are extremely common, therefore, using alternative methods to address these challenges for treatment seems crucial. In the last decade, T cells genetically engineered with Chimeric Antigen Receptor (CAR) treatment for the ALL are largely studied and represent the new era of strategy. According to the Phase I/II clinical trials, this technology results seem very promising and can be used in the next future as an effective and safe treatment for ALL treatment. In this review different generations, challenges, and clinical studies related to chimeric antigen receptor (CAR) T-cells for ALL treatment are discussed.
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Affiliation(s)
- Mohsen Sheykhhasan
- grid.411950.80000 0004 0611 9280Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran ,Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom, Iran
| | - Hamed Manoochehri
- grid.411950.80000 0004 0611 9280Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Paola Dama
- Research Fellow School of Life Sciences, University of Sussex, Brighton, UK.
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Singh S, Khasbage S, Kaur RJ, Sidhu JK, Bhandari B. Chimeric antigen receptor T cell: A cancer immunotherapy. Indian J Pharmacol 2022; 54:226-233. [PMID: 35848695 PMCID: PMC9396692 DOI: 10.4103/ijp.ijp_531_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
During present decade, targeted drug therapy has been the epitome for treatment of cancer. Drugs like Imatinib, a tyrosine kinase receptor inhibitor and Trastuzumab, an human epidermal growth factor receptor-2/neu inhibitor, has been developed and accepted widely for management of chronic myeloid leukaemia and breast cancer respectively. Recent development among the various immunotherapies is adoptive cell transfer (ACT). Research on development of various types of ACT immunotherapy is going on, but so far, Chimeric antigen receptors T cell therapy (CAR-T) has achieved the maximum advancement in terms of clinical development. CARs are the modified receptors that integrates specificity and responsiveness onto immune cells to enhance the recognition of cancer cells. For the CAR-T, the T cells are sequestered from a blood of a participant via apheresis. DNA of particular antigen is injected into harvested T cells to generate CARs on cell surface. Following surface manifestation of receptors, multiplication is carried out in enriched media followed by infusion into patient. After infusion, CAR-T cells targeted and exterminate the cancer cells. Initially, only two drugs targeting CD19 as genetically modified autologous immunotherapy has been approved in CAR-T therapy i.e., Tisagenlecleucel and Axicabtagene Ciloleucel, which are discussed in detail in current review. Recently two more drugs got approval i.e., brexucabtagene ciloleucel and lisocabtagene maraleucel, both are directed against CD19, similar to tisagenlecleucel. CAR-T cell therapy is approved for management of Acute Lymphoblastic Leukaemia, Chronic Lymphocytic Leukaemia and lymphoma. CAR-T cell persistence responsible for effectiveness and safety concerns are barriers for their wide application among patients. Growth factor receptors and cluster of differentiation are new drugs targets that are being explored as effective immunotherapy against cancers.
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Affiliation(s)
- Surjit Singh
- Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India,Address for correspondence: Dr. Surjit Singh, Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India. E-mail:
| | - Sameer Khasbage
- Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Rimple Jeet Kaur
- Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Jaspreet Kaur Sidhu
- Department of Pharmacology, Government Institute of Medical Sciences, Greater Noida, India
| | - Bharti Bhandari
- Department of Physiology, Government Institute of Medical Sciences, Greater Noida, India
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Clinical Studies on Cytokine-Induced Killer Cells: Lessons from Lymphoma Trials. Cancers (Basel) 2021; 13:cancers13236007. [PMID: 34885117 PMCID: PMC8656601 DOI: 10.3390/cancers13236007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/26/2021] [Accepted: 11/27/2021] [Indexed: 01/03/2023] Open
Abstract
Simple Summary Lymphoma is a heterogeneous group of neoplasms including over 70 different subtypes. Its biological characteristic of deriving from lymphoid tissues makes it ideal for immunotherapy. In this paper, we provide insights into lymphoma-specific clinical trials based on cytokine-induced killer (CIK) cell therapy. We also reviewed pre-clinical lymphoma models where CIK cells have been used along with other synergetic tumor-targeting immune modules to improve their therapeutic potential. From a broader perspective, we will highlight that CIK cell therapy has potential, and in this rapidly evolving landscape of cancer therapies its optimization (as a personalized therapeutic approach) will be beneficial in lymphomas. Abstract Cancer is a complex disease where resistance to therapies and relapses often pose a serious clinical challenge. The scenario is even more complicated when the cancer type itself is heterogeneous in nature, e.g., lymphoma, a cancer of the lymphocytes which constitutes more than 70 different subtypes. Indeed, the treatment options continue to expand in lymphomas. Herein, we provide insights into lymphoma-specific clinical trials based on cytokine-induced killer (CIK) cell therapy and other pre-clinical lymphoma models where CIK cells have been used along with other synergetic tumor-targeting immune modules to improve their therapeutic potential. From a broader perspective, we will highlight that CIK cell therapy has potential, and in this rapidly evolving landscape of cancer therapies its optimization (as a personalized therapeutic approach) will be beneficial in lymphomas.
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Palicelli A, Croci S, Bisagni A, Zanetti E, De Biase D, Melli B, Sanguedolce F, Ragazzi M, Zanelli M, Chaux A, Cañete-Portillo S, Bonasoni MP, Soriano A, Ascani S, Zizzo M, Castro Ruiz C, De Leo A, Giordano G, Landriscina M, Carrieri G, Cormio L, Berney DM, Gandhi J, Santandrea G, Bonacini M. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 4: Experimental Treatments in Pre-Clinical Studies (Cell Lines and Mouse Models). Int J Mol Sci 2021; 22:12297. [PMID: 34830179 PMCID: PMC8618402 DOI: 10.3390/ijms222212297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 02/05/2023] Open
Abstract
In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).
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Affiliation(s)
- Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Stefania Croci
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (S.C.); (M.B.)
| | - Alessandra Bisagni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Dario De Biase
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy;
| | - Beatrice Melli
- Fertility Center, Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
- International Doctorate School in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | | | - Moira Ragazzi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Alcides Chaux
- Department of Scientific Research, School of Postgraduate Studies, Norte University, Asunción 1614, Paraguay;
| | - Sofia Cañete-Portillo
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Maria Paola Bonasoni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Alessandra Soriano
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA;
- Gastroenterology Division, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy;
- Haematopathology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Carolina Castro Ruiz
- International Doctorate School in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 41121 Modena, Italy;
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Antonio De Leo
- Molecular Diagnostic Unit, Azienda USL Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy;
| | - Guido Giordano
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Matteo Landriscina
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Giuseppe Carrieri
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Luigi Cormio
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Daniel M. Berney
- Barts Cancer Institute, Queen Mary University of London, London EC1M 5PZ, UK;
| | - Jatin Gandhi
- Department of Pathology and Laboratory Medicine, University of Washington, Seattle, WA 98195, USA;
| | - Giacomo Santandrea
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
- International Doctorate School in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (S.C.); (M.B.)
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Song HW, Lee HS, Kim SJ, Kim HY, Choi YH, Kang B, Kim CS, Park JO, Choi E. Sonazoid-Conjugated Natural Killer Cells for Tumor Therapy and Real-Time Visualization by Ultrasound Imaging. Pharmaceutics 2021; 13:pharmaceutics13101689. [PMID: 34683982 PMCID: PMC8537855 DOI: 10.3390/pharmaceutics13101689] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 01/08/2023] Open
Abstract
Various cell therapy strategies, including chimeric antigen receptor-expressing T or natural killer (NK) cells and cell-mediated drug delivery, have been developed for tumor eradication. However, the efficiency of these strategies against solid tumors remains unclear. We hypothesized that real-time control and visualization of therapeutic cells, such as NK cells, would improve their therapeutic efficacy against solid tumors. In this study, we engineered Sonazoid microbubble-conjugated NK (NK_Sona) cells and demonstrated that they were detectable by ultrasound imaging in real-time and maintained their functions. The Sonazoid microbubbles on the cell membrane did not affect the cytotoxicity and viability of the NK cells in vitro. Additionally, the NK_Sona cells could be visualized by ultrasound imaging and inhibited tumor growth in vivo. Taken together, our findings demonstrate the feasibility of this new approach in the use of therapeutic cells, such as NK cells, against solid tumors.
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Affiliation(s)
- Hyeong-Woo Song
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (H.-W.S.); (H.-S.L.); (S.-J.K.); (H.Y.K.); (Y.H.C.); (B.K.); (C.-S.K.)
| | - Han-Sol Lee
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (H.-W.S.); (H.-S.L.); (S.-J.K.); (H.Y.K.); (Y.H.C.); (B.K.); (C.-S.K.)
- School of Mechanical Engineering, Chonnam National University, Gwangju, 61186, Korea
| | - Seok-Jae Kim
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (H.-W.S.); (H.-S.L.); (S.-J.K.); (H.Y.K.); (Y.H.C.); (B.K.); (C.-S.K.)
- School of Mechanical Engineering, Chonnam National University, Gwangju, 61186, Korea
| | - Ho Yong Kim
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (H.-W.S.); (H.-S.L.); (S.-J.K.); (H.Y.K.); (Y.H.C.); (B.K.); (C.-S.K.)
| | - You Hee Choi
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (H.-W.S.); (H.-S.L.); (S.-J.K.); (H.Y.K.); (Y.H.C.); (B.K.); (C.-S.K.)
| | - Byungjeon Kang
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (H.-W.S.); (H.-S.L.); (S.-J.K.); (H.Y.K.); (Y.H.C.); (B.K.); (C.-S.K.)
- College of AI Convergence, Chonnam National University, Gwangju 61186, Korea
| | - Chang-Sei Kim
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (H.-W.S.); (H.-S.L.); (S.-J.K.); (H.Y.K.); (Y.H.C.); (B.K.); (C.-S.K.)
- School of Mechanical Engineering, Chonnam National University, Gwangju, 61186, Korea
| | - Jong-Oh Park
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (H.-W.S.); (H.-S.L.); (S.-J.K.); (H.Y.K.); (Y.H.C.); (B.K.); (C.-S.K.)
- School of Mechanical Engineering, Chonnam National University, Gwangju, 61186, Korea
- Correspondence: (J.-O.P.); (E.C.)
| | - Eunpyo Choi
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (H.-W.S.); (H.-S.L.); (S.-J.K.); (H.Y.K.); (Y.H.C.); (B.K.); (C.-S.K.)
- School of Mechanical Engineering, Chonnam National University, Gwangju, 61186, Korea
- Correspondence: (J.-O.P.); (E.C.)
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Marofi F, Rahman HS, Al-Obaidi ZMJ, Jalil AT, Abdelbasset WK, Suksatan W, Dorofeev AE, Shomali N, Chartrand MS, Pathak Y, Hassanzadeh A, Baradaran B, Ahmadi M, Saeedi H, Tahmasebi S, Jarahian M. Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients. Stem Cell Res Ther 2021; 12:465. [PMID: 34412685 PMCID: PMC8377882 DOI: 10.1186/s13287-021-02420-8] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/26/2021] [Indexed: 12/20/2022] Open
Abstract
Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.
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Affiliation(s)
- Faroogh Marofi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaimaniyah, Iraq.,Department of Medical Laboratory Sciences, Komar University of Science and Technology, Chaq-Chaq Qularaise, Sulaimaniyah, Iraq
| | - Zaid Mahdi Jaber Al-Obaidi
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Alkafeel, Najaf, 54001, Iraq.,Department of Chemistry and Biochemistry, College of Medicine, University of Kerbala, Karbala, 56001, Iraq
| | | | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia.,Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, 10210, Thailand
| | | | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Yashwant Pathak
- Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA.,Department of Pharmaceutics, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
| | - Ali Hassanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Saeedi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Safa Tahmasebi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy, No. 2, Floor 4 Unit (G401), 69120, Heidelberg, Germany.
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Olbrich H, Theobald SJ, Slabik C, Gerasch L, Schneider A, Mach M, Shum T, Mamonkin M, Stripecke R. Adult and Cord Blood-Derived High-Affinity gB-CAR-T Cells Effectively React Against Human Cytomegalovirus Infections. Hum Gene Ther 2021; 31:423-439. [PMID: 32159399 PMCID: PMC7194322 DOI: 10.1089/hum.2019.149] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Human cytomegalovirus (HCMV) reactivations are associated with lower overall survival after transplantations. Adoptive transfer of HCMV-reactive expanded or selected T cells can be applied as a compassionate use, but requires that the human leukocyte antigen-matched donor provides memory cells against HCMV. To overcome this, we developed engineered T cells expressing chimeric antigen receptors (CARs) targeted against the HCMV glycoprotein B (gB) expressed upon viral reactivation. Single-chain variable fragments (scFvs) derived from a human high-affinity gB-specific neutralizing monoclonal antibody (SM5-1) were fused to CARs with 4-1BB (BBL) or CD28 (28S) costimulatory domains and subcloned into retroviral vectors. CD4+ and CD8+ T cells obtained from HCMV-seronegative adult blood or cord blood (CB) transduced with the vectors efficiently expressed the gB-CARs. The specificity and potency of gB-CAR-T cells were demonstrated and compared in vitro using the following: 293T cells expressing gB, and with mesenchymal stem cells infected with a HCMV TB40 strain expressing Gaussia luciferase (HCMV/GLuc). BBL-gB-CAR-T cells generated with adult or CB demonstrated significantly higher in vitro activation and cytotoxicity performance than 28-gB-CAR-T cells. Nod.Rag.Gamma (NRG) mice transplanted with human CB CD34+ cells with long-term human immune reconstitution were used to model HCMV/GLuc infection in vivo by optical imaging analyses. One week after administration, response to BBL-gB-CAR-T cell therapy was observed for 5/8 mice, defined by significant reduction of the bioluminescent signal in relation to untreated controls. Response to therapy was sporadically associated with CAR detection in spleen. Thus, exploring scFv derived from the high-affinity gB-antibody SM5-1 and the 4-1BB signaling domain for CAR design enabled an in vitro high on-target effect and cytotoxicity and encouraging results in vivo. Therefore, gB-CAR-T cells can be a future clinical option for treatment of HCMV reactivations, particularly when memory T cells from the donors are not available.
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Affiliation(s)
- Henning Olbrich
- Laboratory of Regenerative Immune Therapies Applied, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Sebastian J Theobald
- Laboratory of Regenerative Immune Therapies Applied, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Constanze Slabik
- Laboratory of Regenerative Immune Therapies Applied, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Laura Gerasch
- Laboratory of Regenerative Immune Therapies Applied, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Andreas Schneider
- Laboratory of Regenerative Immune Therapies Applied, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Michael Mach
- Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas Shum
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.,Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas
| | - Maksim Mamonkin
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.,Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
| | - Renata Stripecke
- Laboratory of Regenerative Immune Therapies Applied, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
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Li M, Xie D, Tang X, Yang C, Shen Y, Zhou H, Deng W, Liu J, Cai S, Bai L, Wang Y. Phototherapy Facilitates Tumor Recruitment and Activation of Natural Killer T cells for Potent Cancer Immunotherapy. NANO LETTERS 2021; 21:6304-6313. [PMID: 34264088 DOI: 10.1021/acs.nanolett.1c02238] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Adoptively transferred natural killer T (NKT) cells confer distinct cancer surveillance without causing obvious side effects, making them a promising candidate for cancer immunotherapy. However, their therapeutic efficacy is limited by inefficient tumor infiltration and inadequate activation in an immunosuppressive tumor microenvironment. To overcome these obstacles, we develop a strategy of using photothermal therapy (PTT) to promote the antitumor ability of adoptively transferred NKT cells. The transferred NKT cells are efficiently recruited to PTT-treated tumors in response to PTT-created inflammation. Moreover, PTT treatment promotes the activation of NKT cells and enhances the NKT cell-initiated immune cascade. As a consequence, the combined therapy of PTT plus NKT cell transfer exhibits excellent growth inhibition of local tumors. Moreover, it efficiently rejects distant tumors and elicits long-term immunological memory to prevent tumor recurrence. Overall, the current study opens new paths to the clinical translation of NKT cells for cancer immunotherapy.
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Affiliation(s)
- Min Li
- Department of Interventional Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Di Xie
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Xinfeng Tang
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Chen Yang
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Yanqiong Shen
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Han Zhou
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Wuxian Deng
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Jiwei Liu
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Shanbao Cai
- Department of Orthopedic Surgery, Anhui Provincial Cancer Hospital, West Branch of the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Li Bai
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Yucai Wang
- Department of Interventional Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
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Diamant G, Simchony Goldman H, Gasri Plotnitsky L, Roitman M, Shiloach T, Globerson-Levin A, Eshhar Z, Haim O, Pencovich N, Grossman R, Ram Z, Volovitz I. T Cells Retain Pivotal Antitumoral Functions under Tumor-Treating Electric Fields. THE JOURNAL OF IMMUNOLOGY 2021; 207:709-719. [PMID: 34215656 DOI: 10.4049/jimmunol.2100100] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/28/2021] [Indexed: 11/19/2022]
Abstract
Tumor-treating fields (TTFields) are a localized, antitumoral therapy using alternating electric fields, which impair cell proliferation. Combining TTFields with tumor immunotherapy constitutes a rational approach; however, it is currently unknown whether TTFields' locoregional effects are compatible with T cell functionality. Healthy donor PBMCs and viably dissociated human glioblastoma samples were cultured under either standard or TTFields conditions. Select pivotal T cell functions were measured by multiparametric flow cytometry. Cytotoxicity was evaluated using a chimeric Ag receptor (CAR)-T-based assay. Glioblastoma patient samples were acquired before and after standard chemoradiation or standard chemoradiation + TTFields treatment and examined by immunohistochemistry and by RNA sequencing. TTFields reduced the viability of proliferating T cells, but had little or no effect on the viability of nonproliferating T cells. The functionality of T cells cultured under TTFields was retained: they exhibited similar IFN-γ secretion, cytotoxic degranulation, and PD1 upregulation as controls with similar polyfunctional patterns. Glioblastoma Ag-specific T cells exhibited unaltered viability and functionality under TTFields. CAR-T cells cultured under TTFields exhibited similar cytotoxicity as controls toward their CAR target. Transcriptomic analysis of patients' glioblastoma samples revealed a significant shift in the TTFields-treated versus the standard-treated samples, from a protumoral to an antitumoral immune signature. Immunohistochemistry of samples before and after TTFields treatment showed no reduction in T cell infiltration. T cells were found to retain key antitumoral functions under TTFields settings. Our data provide a mechanistic insight and a rationale for ongoing and future clinical trials that combine TTFields with immunotherapy.
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Affiliation(s)
- Gil Diamant
- The Cancer Immunotherapy Laboratory, Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University Tel-Aviv, Israel.,Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and
| | - Hadar Simchony Goldman
- The Cancer Immunotherapy Laboratory, Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University Tel-Aviv, Israel
| | - Lital Gasri Plotnitsky
- The Cancer Immunotherapy Laboratory, Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University Tel-Aviv, Israel
| | - Marina Roitman
- The Cancer Immunotherapy Laboratory, Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University Tel-Aviv, Israel
| | - Tamar Shiloach
- Laboratory for Cancer Research and Immunotherapy, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Anat Globerson-Levin
- Laboratory for Cancer Research and Immunotherapy, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Zelig Eshhar
- Laboratory for Cancer Research and Immunotherapy, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Oz Haim
- Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and
| | - Niv Pencovich
- Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and
| | - Rachel Grossman
- Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and
| | - Zvi Ram
- Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and
| | - Ilan Volovitz
- The Cancer Immunotherapy Laboratory, Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University Tel-Aviv, Israel; .,Neurosurgery Department, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and
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40
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Alvarez-Fernández C, Escribà-Garcia L, Caballero AC, Escudero-López E, Ujaldón-Miró C, Montserrat-Torres R, Pujol-Fernández P, Sierra J, Briones J. Memory stem T cells modified with a redesigned CD30-chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma. Clin Transl Immunology 2021; 10:e1268. [PMID: 33968404 PMCID: PMC8082716 DOI: 10.1002/cti2.1268] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 12/18/2020] [Accepted: 03/04/2021] [Indexed: 01/03/2023] Open
Abstract
Objectives Adoptive cell therapy (ACT) with mature T cells modified with a chimeric antigen receptor has demonstrated improved outcome for B‐cell malignancies. However, its application for others such as Hodgkin lymphoma remains a clinical challenge. CD30 antigen, expressed in Hodgkin lymphoma cells, is absent in most healthy tissues, representing an ideal target of ACT for this disease. Despite that, efficacy of CD30‐chimeric antigen receptor (CAR) T cells for Hodgkin lymphoma remains modest. Here, we have developed and tested a novel CD30‐CAR T to improve efficacy of CD30‐CAR therapy, using a targeting epitope within the non‐cleavable part of CD30 receptor, and memory stem T cells (TSCM) to improve engraftment, persistence and antitumor activity. Methods TSCM‐like cultures were generated and expanded ex vivo and transduced at day 1 or 2 with a lentiviral vector encoding the CD30‐CAR. Therapeutic in vivo experiments were performed using NSG mice injected with L540 (sc) or L428 (iv) and treated with CD30‐CAR T cells when the tumor was established. Results CD30‐CAR TSCM‐like cells generated and expanded ex vivo, despite CD30 expression and fratricide killing of CD30+ CAR T cells, were not impaired by soluble CD30 and completely eradicated Hodgkin lymphoma in vivo, showing high persistence and long‐lasting immunity. In addition, highly enriched CD30‐CAR TSCM‐like products confer a survival advantage in vivo, in contrast to more differentiated CAR T cells, with higher tumor infiltration and enhanced antitumor effect. Conclusion This study supports the use of a refined CD30‐CAR T cells with highly enriched TSCM‐like products to improve clinical efficacy of CAR T for Hodgkin lymphoma.
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Affiliation(s)
- Carmen Alvarez-Fernández
- Hematology Service Hospital de la Santa Creu y Sant Pau Barcelona Spain.,Laboratory of Experimental Hematology-IIB Institut Recerca Hospital de la Santa Creu y Sant Pau Barcelona Spain.,José Carreras Leukemia Research Institute Barcelona Spain
| | - Laura Escribà-Garcia
- Hematology Service Hospital de la Santa Creu y Sant Pau Barcelona Spain.,Laboratory of Experimental Hematology-IIB Institut Recerca Hospital de la Santa Creu y Sant Pau Barcelona Spain.,José Carreras Leukemia Research Institute Barcelona Spain
| | - A C Caballero
- Hematology Service Hospital de la Santa Creu y Sant Pau Barcelona Spain.,Laboratory of Experimental Hematology-IIB Institut Recerca Hospital de la Santa Creu y Sant Pau Barcelona Spain.,José Carreras Leukemia Research Institute Barcelona Spain.,Autonomous University of Barcelona Barcelona Spain
| | - Eva Escudero-López
- Hematology Service Hospital de la Santa Creu y Sant Pau Barcelona Spain.,Laboratory of Experimental Hematology-IIB Institut Recerca Hospital de la Santa Creu y Sant Pau Barcelona Spain.,José Carreras Leukemia Research Institute Barcelona Spain.,Autonomous University of Barcelona Barcelona Spain
| | - Cristina Ujaldón-Miró
- Hematology Service Hospital de la Santa Creu y Sant Pau Barcelona Spain.,Laboratory of Experimental Hematology-IIB Institut Recerca Hospital de la Santa Creu y Sant Pau Barcelona Spain.,José Carreras Leukemia Research Institute Barcelona Spain.,Autonomous University of Barcelona Barcelona Spain
| | - Rosanna Montserrat-Torres
- Hematology Service Hospital de la Santa Creu y Sant Pau Barcelona Spain.,Laboratory of Experimental Hematology-IIB Institut Recerca Hospital de la Santa Creu y Sant Pau Barcelona Spain.,José Carreras Leukemia Research Institute Barcelona Spain
| | - Paula Pujol-Fernández
- Hematology Service Hospital de la Santa Creu y Sant Pau Barcelona Spain.,Laboratory of Experimental Hematology-IIB Institut Recerca Hospital de la Santa Creu y Sant Pau Barcelona Spain.,José Carreras Leukemia Research Institute Barcelona Spain
| | - Jorge Sierra
- Hematology Service Hospital de la Santa Creu y Sant Pau Barcelona Spain.,José Carreras Leukemia Research Institute Barcelona Spain.,Autonomous University of Barcelona Barcelona Spain
| | - Javier Briones
- Hematology Service Hospital de la Santa Creu y Sant Pau Barcelona Spain.,Laboratory of Experimental Hematology-IIB Institut Recerca Hospital de la Santa Creu y Sant Pau Barcelona Spain.,José Carreras Leukemia Research Institute Barcelona Spain.,Autonomous University of Barcelona Barcelona Spain
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41
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Shou X, Zhang H, Wu D, Zhong L, Ni D, Kong T, Zhao Y, Zhao Y. Antigen-Presenting Hybrid Colloidal Crystal Clusters for Promoting T cells Expansion. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2006955. [PMID: 33711196 DOI: 10.1002/smll.202006955] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 01/03/2021] [Indexed: 06/12/2023]
Abstract
T cell based-immunotherapy has been a powerful strategy to eradicate tumor cells in clinical trials. Effectively expanding the therapeutic T cells for clinical demand is still a challenge. Here, artificial antigen-presenting scaffolds are created for T cell ex vivo expansion. The antigen-presenting hybrid colloidal crystal clusters (HCCCs) with multiple stimuli are generated by internal encapsulation with prosurvival cytokines and surface decoration with activating antibodies to CD3ε and CD28, respectively. With the large loading capacity endowed by their abundant nanoporous structures, the antigen-presenting HCCCs can constantly release prosurvival cytokine IL-2. It is found that following the direct and multiple stimulations, the antigen-presenting HCCCs can effectively promote the expansion of T cells, which exhibits robust antitumor activity in vitro. Thus, the antigen-presenting HCCCs provide a novel expansion platform for clinical manufacturing of T cells.
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Affiliation(s)
- Xin Shou
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Hui Zhang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Dan Wu
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325001, China
| | - Liping Zhong
- National Center for International Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Theranostics, Guangxi Medical University, Guangxi, 530021, China
| | - Dong Ni
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Tiantian Kong
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Yongxiang Zhao
- National Center for International Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Theranostics, Guangxi Medical University, Guangxi, 530021, China
| | - Yuanjin Zhao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
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42
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Alhakamy NA, Curiel DT, Berkland CJ. The era of gene therapy: From preclinical development to clinical application. Drug Discov Today 2021; 26:1602-1619. [PMID: 33781953 DOI: 10.1016/j.drudis.2021.03.021] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/09/2020] [Accepted: 03/21/2021] [Indexed: 12/16/2022]
Abstract
Three decades of promise have culminated in the development of gene therapies that can be applied to a broad range of human diseases. After a brief history, we provide an overview of gene therapy types and delivery methods, gene editing technologies, regulatory affairs, clinical trials, approved products, ongoing challenges, and future goals. Information on clinical trials of candidates and on approved products for gene therapy developed between 1988 and 2020 is systematically collated. To obtain this global information, we scanned and reviewed more than 46,000 records of clinical trials from 17 clinical trial database providers. The medical benefits of transformative gene therapies are gradually being accepted by payors, and a significant increase in the number of gene therapy clinical trials and approved gene therapy products has resulted.
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Affiliation(s)
- Nabil A Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA
| | - David T Curiel
- Department of Radiation Oncology, School of Medicine, Washington University, St. Louis, MO 63108, USA
| | - Cory J Berkland
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA; Department of Chemical & Petroleum Engineering, University of Kansas, Lawrence, KS 66047, USA.
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43
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Tarach P, Janaszewska A. Recent Advances in Preclinical Research Using PAMAM Dendrimers for Cancer Gene Therapy. Int J Mol Sci 2021; 22:2912. [PMID: 33805602 PMCID: PMC7999260 DOI: 10.3390/ijms22062912] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 12/16/2022] Open
Abstract
Carriers of genetic material are divided into vectors of viral and non-viral origin. Viral carriers are already successfully used in experimental gene therapies, but despite advantages such as their high transfection efficiency and the wide knowledge of their practical potential, the remaining disadvantages, namely, their low capacity and complex manufacturing process, based on biological systems, are major limitations prior to their broad implementation in the clinical setting. The application of non-viral carriers in gene therapy is one of the available approaches. Poly(amidoamine) (PAMAM) dendrimers are repetitively branched, three-dimensional molecules, made of amide and amine subunits, possessing unique physiochemical properties. Surface and internal modifications improve their physicochemical properties, enabling the increase in cellular specificity and transfection efficiency and a reduction in cytotoxicity toward healthy cells. During the last 10 years of research on PAMAM dendrimers, three modification strategies have commonly been used: (1) surface modification with functional groups; (2) hybrid vector formation; (3) creation of supramolecular self-assemblies. This review describes and summarizes recent studies exploring the development of PAMAM dendrimers in anticancer gene therapies, evaluating the advantages and disadvantages of the modification approaches and the nanomedicine regulatory issues preventing their translation into the clinical setting, and highlighting important areas for further development and possible steps that seem promising in terms of development of PAMAM as a carrier of genetic material.
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MESH Headings
- Biocompatible Materials/administration & dosage
- Biocompatible Materials/chemical synthesis
- Dendrimers/administration & dosage
- Dendrimers/chemical synthesis
- Gene Expression Regulation, Neoplastic
- Gene Transfer Techniques
- Genetic Therapy/methods
- Government Regulation
- Humans
- MicroRNAs/administration & dosage
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Nanomedicine/legislation & jurisprudence
- Nanomedicine/methods
- Nanoparticles/administration & dosage
- Nanoparticles/chemistry
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Neoplasms/genetics
- Neoplasms/metabolism
- Neoplasms/pathology
- Neoplasms/therapy
- Oligonucleotides, Antisense/administration & dosage
- Oligonucleotides, Antisense/genetics
- Oligonucleotides, Antisense/metabolism
- Plasmids/administration & dosage
- Plasmids/chemistry
- Plasmids/metabolism
- RNA, Messenger/administration & dosage
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Small Interfering/administration & dosage
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Surface Properties
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Affiliation(s)
- Piotr Tarach
- Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland;
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Bhushan M, Kumar KR. Post-CAR-T cell therapy presenting as proteinaceous lymphadenopathy. HUMAN PATHOLOGY: CASE REPORTS 2021. [DOI: 10.1016/j.ehpc.2021.200475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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45
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Arias J, Yu J, Varshney M, Inzunza J, Nalvarte I. Hematopoietic stem cell- and induced pluripotent stem cell-derived CAR-NK cells as reliable cell-based therapy solutions. Stem Cells Transl Med 2021; 10:987-995. [PMID: 33634954 PMCID: PMC8235144 DOI: 10.1002/sctm.20-0459] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 01/06/2021] [Accepted: 01/30/2021] [Indexed: 02/06/2023] Open
Abstract
Hematopoietic stem cell‐ (HSC) and induced pluripotent stem (iPS) cell‐derived natural killer (NK) cells containing engineered functions, such as chimeric antigen receptors (CAR), offer great promise for the treatment of seemingly incurable oncological malignancies. Today, some of the main challenges of CAR cell‐based therapeutics are the long manufacturing time and safety of the cell sources used. Additional challenges include avoiding graft vs host disease (GVHD) and cytokine release syndrome (CRS). Here, we show compelling evidence for the use of NK cell therapeutics as a reliable off‐the‐shelf option, as they address key issues. Furthermore, we highlight how iPS cells and directed differentiation toward HSC and NK cells address industrial scalability and safety.
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Affiliation(s)
- Jonathan Arias
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.,Bright SA, Luxembourg, Luxembourg
| | - Jingwei Yu
- Bright SA, Luxembourg, Luxembourg.,Tianjin Medical University Cancer Institute and Hospital, Department of Lymphoma, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Mukesh Varshney
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.,JoinCells Nordic AB, Karolinska Institutet Science Park AB, Huddinge, Sweden
| | - Jose Inzunza
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.,JoinCells Nordic AB, Karolinska Institutet Science Park AB, Huddinge, Sweden
| | - Ivan Nalvarte
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.,JoinCells Nordic AB, Karolinska Institutet Science Park AB, Huddinge, Sweden
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46
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Tanaka J. Recent advances in cellular therapy for malignant lymphoma. Cytotherapy 2021; 23:662-671. [PMID: 33558145 DOI: 10.1016/j.jcyt.2020.12.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/25/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023]
Abstract
Cellular therapies for malignant lymphoma include autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and adaptive cellular therapy using EBV-specific T cells, cytokine-induced killer (CIK) cells, NKT cells, NK cells, chimeric antigen receptor T (CAR-T) cells and chimeric antigen receptor NK (CAR-NK) cells. In this review we discusses recent advances of these cellular therapies and consider ways to optimize these therapies. Not only a single strategy using one of these cellular therapies, but also multi-disciplinary treatment combines with antibodies, such as an anti-tumor antibody and an immune checkpoint antibody, may be more effective for relapsed and refractory lymphoma.
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Affiliation(s)
- Junji Tanaka
- Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
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47
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Salah A, Li Y, Wang H, Qi N, Wu Y. Macrophages as a Double-Edged Weapon: The Use of Macrophages in Cancer Immunotherapy and Understanding the Cross-Talk Between Macrophages and Cancer. DNA Cell Biol 2021; 40:429-440. [PMID: 33481665 DOI: 10.1089/dna.2020.6087] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Macrophages (Mϕs) play an essential role in maintaining body homeostasis. They perform dual functions produced by different subtypes. Mϕs not only fight against pathogens and foreign bodies such as bacteria or cancer cells but also participate in healing and repairing damaged tissue since they maintain both proinflammatory and anti-inflammatory effects sequentially. Tumors possess the ability to polarize Mϕs from proinflammatory M1 subtype to anti-inflammatory M2-like Mϕs called tumor-associated macrophages, which, in turn, help the tumors to acquire cancer hallmarks. Consequently, this polarization allows tumors to grow and spread. In this light, Mϕs have been a subject of intense study, and researchers have developed protocols to derive different Mϕs subtypes either as a new state-of-the-art therapeutic approach or to understand the cross-talk between cancer and Mϕs. In this review, we present the use of primary Mϕs in adoptive immunotherapy for cancer, illustrate the reciprocating interplay between cancer and Mϕs, and the resulting structural and functional change on both cell types. Furthermore, we summarize the recent cutting-edge approaches of using Mϕs in cancer immunotherapy.
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Affiliation(s)
- Ahmed Salah
- Department of Biochemistry and Molecular Biology, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, P.R. China
| | - Yanqin Li
- Department of Biochemistry and Molecular Biology, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, P.R. China
| | - Hao Wang
- Hangzhou Biaomo Biosciences Co., Ltd., Hangzhou, P.R. China.,Asia Stem Cell Therapies Co., Limited, Shanghai, P.R. China
| | - Nianmin Qi
- Hangzhou Biaomo Biosciences Co., Ltd., Hangzhou, P.R. China.,Asia Stem Cell Therapies Co., Limited, Shanghai, P.R. China
| | - Yuehong Wu
- Department of Biochemistry and Molecular Biology, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, P.R. China
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48
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Al-Hashemi H, Rahman SHA, Shabeeb Z. Expression of immune checkpoint molecules in Iraqi acute myeloid leukemia patients. IRAQI JOURNAL OF HEMATOLOGY 2021. [DOI: 10.4103/ijh.ijh_46_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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49
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Han D, Xu Z, Zhuang Y, Ye Z, Qian Q. Current Progress in CAR-T Cell Therapy for Hematological Malignancies. J Cancer 2021; 12:326-334. [PMID: 33391429 PMCID: PMC7738987 DOI: 10.7150/jca.48976] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/20/2020] [Indexed: 12/11/2022] Open
Abstract
Immunotherapies, such as monoclonal antibody therapy and checkpoint inhibitor therapy, have shown inspiring clinical effects for the treatment of cancer. Chimeric antigen receptor T (CAR-T) cells therapy was an efficacious therapeutic approach treating hematological malignancies and encouraging results have been achieved. Three kinds of CAR-T cell therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), were approved for clinical application in 2017 and Tecartus (brexucabtagene autoleucel) was approved in 2020. Despite some progress have been made in treating multiple hematologic tumors, threats still remain for the application of CAR-T cell therapy considering its toxicities and gaps in knowledge. To further comprehend present research status and trends, the review concentrates on CAR-T technologies, applications, adverse effects and safety measures about CAR-T cell therapy in hematological neoplasms. We believe that CAR-T cell therapy will exhibit superior safety and efficacy in the future and have potential to be a mainstream therapeutic choice for the elimination of hematologic tumor.
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Affiliation(s)
- Donglei Han
- Henan Cell Therapy Group Co. LTD, Zhengzhou, Henan, China
| | - Zenghui Xu
- Henan Cell Therapy Group Co. LTD, Zhengzhou, Henan, China.,Shanghai University Mengchao Cancer Hospital, Shanghai, China.,Shanghai Baize Medical Laboratory, Shanghai, China
| | - Yuan Zhuang
- Shanghai Baize Medical Laboratory, Shanghai, China
| | - Zhenlong Ye
- Henan Cell Therapy Group Co. LTD, Zhengzhou, Henan, China.,Shanghai University Mengchao Cancer Hospital, Shanghai, China.,Shanghai Baize Medical Laboratory, Shanghai, China
| | - Qijun Qian
- Henan Cell Therapy Group Co. LTD, Zhengzhou, Henan, China.,Shanghai University Mengchao Cancer Hospital, Shanghai, China.,Shanghai Baize Medical Laboratory, Shanghai, China
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50
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Yilmaz A, Cui H, Caligiuri MA, Yu J. Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy. J Hematol Oncol 2020; 13:168. [PMID: 33287875 PMCID: PMC7720606 DOI: 10.1186/s13045-020-00998-9] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022] Open
Abstract
Natural killer (NK) cells are a critical component of the innate immune system. Chimeric antigen receptors (CARs) re-direct NK cells toward tumor cells carrying corresponding antigens, creating major opportunities in the fight against cancer. CAR NK cells have the potential for use as universal CAR cells without the need for human leukocyte antigen matching or prior exposure to tumor-associated antigens. Exciting data from recent clinical trials have renewed interest in the field of cancer immunotherapy due to the potential of CAR NK cells in the production of "off-the-shelf" anti-cancer immunotherapeutic products. Here, we provide an up-to-date comprehensive overview of the recent advancements in key areas of CAR NK cell research and identify under-investigated research areas. We summarize improvements in CAR design and structure, advantages and disadvantages of using CAR NK cells as an alternative to CAR T cell therapy, and list sources to obtain NK cells. In addition, we provide a list of tumor-associated antigens targeted by CAR NK cells and detail challenges in expanding and transducing NK cells for CAR production. We additionally discuss barriers to effective treatment and suggest solutions to improve CAR NK cell function, proliferation, persistence, therapeutic effectiveness, and safety in solid and liquid tumors.
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Affiliation(s)
- Ahmet Yilmaz
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Hanwei Cui
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Michael A Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 E. Duarte Road, KCRB, Bldg. 158, 3rd Floor, Room 3017, Los Angeles, CA, 91010, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
- Department of Immuno-Oncology, City of Hope Beckman Research Institute, Los Angeles, CA, 91010, USA
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, Los Angeles, CA, 91010, USA
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 E. Duarte Road, KCRB, Bldg. 158, 3rd Floor, Room 3017, Los Angeles, CA, 91010, USA.
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
- Department of Immuno-Oncology, City of Hope Beckman Research Institute, Los Angeles, CA, 91010, USA.
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, Los Angeles, CA, 91010, USA.
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