Bispecific Chimeric Antigen Receptor T Cell Therapy for B Cell Malignancies and Multiple Myeloma

Cronk, Robert J.; Zurko, Joanna; Shah, Nirav N.

doi:10.3390/cancers12092523

Cited by 39 publications

(23 citation statements)

References 65 publications

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“…Furthermore, as with single-targeting CARs, the dual/multi-targeting CARs can also elicit selective pressure that could be stronger due to enhanced immune response, resulting in simultaneous escape of both antigens. Beyond technical complexities, another apparent challenge is the risk of high-grade CRS that comes with augmented T-cell activation from concurrent antigen targeting 75 .…”

Section: Technological Advances Of Car T-cell Manufacturing In Myelomamentioning

confidence: 99%

CAR T-cell therapy in multiple myeloma: more room for improvement

2021

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The emergence of various novel therapies over the last decade has changed the therapeutic landscape for multiple myeloma. While the clinical outcomes have improved significantly, the disease remains incurable, typically in patients with relapsed and refractory disease. Chimeric antigen receptor (CAR) T-cell therapies have achieved remarkable clinical success in B-cell malignancies. This scope of research has more recently been extended to the field of myeloma. While B-cell maturation antigen (BCMA) is currently the most well-studied CAR T antigen target in this disease, many other antigens are also undergoing intensive investigations. Some studies have shown encouraging results, whereas some others have demonstrated unfavorable results due to reasons such as toxicity and lack of clinical efficacy. Herein, we provide an overview of CAR T-cell therapies in myeloma, highlighted what has been achieved over the past decade, including the latest updates from ASH 2020 and discussed some of the challenges faced. Considering the current hits and misses of CAR T therapies, we provide a comprehensive analysis on the current manufacturing technologies, and deliberate on the future of CAR T-cell domain in MM.

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Section: Technological Advances Of Car T-cell Manufacturing In Myelomamentioning

confidence: 99%

CAR T-cell therapy in multiple myeloma: more room for improvement

2021

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“…Despite limited evidence on the failure of response due to BCMA escape among trials with Si-CAR T-cell therapy targeting BCMA, the combination of BCMA CAR and a second CAR is still being explored in MM [11,12], most of which adopt cocktail/sequential infusion of BCMA Si-CAR T cells and other Si-CAR T cells. Bi-CAR T-cell therapy with bivalent CAR recognizing BCMA/CD19 [82] and BCMA/CD38 [38] have advanced into clinics, while BCMA/CS1(SLAMF7) [42,43] and BCMA/GPRC5D Bi-CAR T-cell therapies [39] are forthcoming, as they were found to be effective in preclinical models.…”

Section: Clinical Efficacy Of Dual-targeting Car T-cell Therapy For H...mentioning

confidence: 99%

Current Status and Perspectives of Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Hematological Malignancies

Xie¹,

Zhou

et al. 2022

Cancers

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Single-targeted chimeric antigen receptor (CAR) T cells tremendously improve outcomes for patients with relapsed/refractory hematological malignancies and are considered a breakthrough therapy. However, over half of treated patients experience relapse or refractory disease, with antigen escape being one of the main contributing mechanisms. Dual-targeting CAR T-cell therapy is being developed to minimize the risk of relapse or refractory disease. Preclinical and clinical data on five categories of dual-targeting CAR T-cell therapies and approximately fifty studies were summarized to offer insights and support the development of dual-targeting CAR T-cell therapy for hematological malignancies. The clinical efficacy (durability and survival) is validated and the safety profiles of dual-targeting CAR T-cell therapy are acceptable, although there is still room for improvement in the bispecific CAR structure. It is one of the best approaches to optimize the bispecific CAR structure by boosting T-cell transduction efficiency and leveraging evidence from preclinical activity and clinical efficacy.

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“…Another strategy described involves the generation of a bi-cistronic CAR-T line with each CAR-T expressing two different CAR constructs that each have single-antigen specificity. Lastly, the generation of tandem CAR-Ts has been described, with the infusion of a single CAR-T line that expresses a single CAR construct that has an extracellular domain with scFv portions in a number of potential configurations capable of recognizing two or more antigens [51,52].…”

Section: Multi-specific Carsmentioning

confidence: 99%

Cellular Therapy Updates in B-Cell Lymphoma: The State of the CAR-T

Crees

Ghobadi

2021

Cancers

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Non-Hodgkin Lymphoma accounts for >460,000 cases and >240,000 deaths globally and >77,000 cases and >20,000 deaths in the U.S. annually, with ~85% of cases being B-cell malignancies. Until recently, patients with relapsed/refractory B-cell lymphoma following standard chemotherapy in combination with anti-CD20 monoclonal antibodies and autologous stem cell transplantation experienced a median overall survival (OS) of <6 months. However, with the approval of four different CD-19 CAR-T therapies between 2017 and 2021, approximately 60–80% of patients receiving CAR-T therapy now achieve an objective response with >3 years median OS. Here, we review the current state of the art of CD19 CAR-T therapies for B-cell lymphomas, focusing on current updates in US FDA-approved products, along with their associated efficacy and toxicities. Lastly, we highlight a selection of promising clinical developments in the field, including various novel strategies to increase CAR-T therapy efficacy while mitigating toxicity.

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Bispecific Chimeric Antigen Receptor T Cell Therapy for B Cell Malignancies and Multiple Myeloma

Cited by 39 publications

References 65 publications

CAR T-cell therapy in multiple myeloma: more room for improvement

CAR T-cell therapy in multiple myeloma: more room for improvement

Current Status and Perspectives of Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Hematological Malignancies

Cellular Therapy Updates in B-Cell Lymphoma: The State of the CAR-T

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