CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells

O’Neal, Julie; Ritchey, Julie; Cooper, Matthew; Niswonger, Jessica; Gonzalez, Luisalberto; Street, Emily; Rettig, Michael P.; Gladney, Susan W; Gehrs, Leah; Abboud, Ramzi; Prior, Julie L.; Haas, Gabriel; Jayasinghe, Reyka G.; Ding, Li; Ghobadi, Armin; Vij, Ravi; DiPersio, John F.

doi:10.1038/s41375-022-01559-4

Cited by 29 publications

(24 citation statements)

References 33 publications

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“…We have already discussed a number of other potential antigens in the context of concurrent dual antigen targeting alongside BCMA ( 34 , 35 , 37 – 42 ). However, several CAR-T therapies that bypass BCMA entirely by targeting other antigens instead have been studied in myeloma as well ( 10 , 45 , 46 , 157 – 163 ). As more patients are exposed to BCMA-directed therapies and develop disease relapse thereafter, particularly in the setting of BCMA allelic loss, these types of CAR-T therapies targeting non-BCMA antigens will become increasingly critical.…”

Section: Discussionmentioning

confidence: 99%

“…Many strategies are under development to continue improving “under the hood” CAR signaling once the receptor binds its target. For example, third-generation CARs contain more than one co-stimulatory domain with the goal of more potently activating T cells ( 9 , 10 ). Similarly, adding a chimeric CD38-binding costimulatory receptor to a BCMA-binding CAR may potentiate the activity and persistence of CAR-T cells ( 11 ).…”

Section: Stronger Engines: More Potent Antigen Targetingmentioning

confidence: 99%

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Innovation in BCMA CAR-T therapy: Building beyond the Model T

2022

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Autologous chimeric antigen receptor T-cell (CAR-T) therapies targeting B-cell maturation antigen (BCMA) have revolutionized the field of multiple myeloma in the same way that the Ford Model T revolutionized the original CAR world a century ago. However, we are only beginning to understand how to improve the efficacy and usability of these cellular therapies. In this review, we explore three automotive analogies for innovation with BCMA CAR-T therapies: stronger engines, better mileage, and hassle-free delivery. Firstly, we can build stronger engines in terms of BCMA targeting: improved antigen binding, tools to modulate antigen density, and armoring to better reach the antigen itself. Secondly, we can improve “mileage” in terms of response durability through ex vivo CAR design and in vivo immune manipulation. Thirdly, we can implement hassle-free delivery through rapid manufacturing protocols and off-the-shelf products. Just as the Model T set a benchmark for car manufacturing over 100 years ago, idecabtagene vicleucel and ciltacabtagene autoleucel have now set the starting point for BCMA CAR-T therapy with their approvals. As with any emerging technology, whether automotive or cellular, the best in innovation and optimization is yet to come.

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Section: Discussionmentioning

confidence: 99%

Section: Stronger Engines: More Potent Antigen Targetingmentioning

confidence: 99%

Innovation in BCMA CAR-T therapy: Building beyond the Model T

2022

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“…Patients who relapsed after receiving BCMA CAR-T cells may benefit from treatment with SLAMF7 CAR-T cells. SLAMF7 CAR-T cells demonstrated its anti-myeloma-killing effect in mouse models [153]. Clinical trials targeting SLAMF7 are ongoing (NCT03958656, NCT04499339).…”

Section: Multiple Myeloma (Mm)mentioning

confidence: 99%

Tumor buster - where will the CAR-T cell therapy ‘missile’ go?

Zhang

Cao

et al. 2022

Mol Cancer

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Chimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME) limit their use of it. Target selection is the most critical aspect in determining the prognosis of patients receiving this treatment. This review provides a comprehensive summary of all therapeutic targets used in the clinic or shown promising potential. We summarize CAR-T cell therapies’ clinical trials, applications, research frontiers, and limitations in treating different cancers. We also explore coping strategies when encountering sub-optimal tumor-associated antigens (TAA) or TAA loss. Moreover, the importance of CAR-T cell therapy in cancer immunotherapy is emphasized.

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“…70 Another potential non-BCMA target is CS1 (SLAMF7) which is highly expressed on MM cells. 71 Preclinical studies of CS1 CAR T-cells have demonstrated in-vitro and in-vivo anti-myeloma cell kill in mouse models, although expression of CS1 on CD8+ T-cells led to fratricide. 71 Several early phase clinical trials are assessing the maximum tolerated dose, safety, and efficacy of CS1 CAR T-cells in RRMM.…”

Section: Non-bcma Targetsmentioning

confidence: 99%

“…71 Preclinical studies of CS1 CAR T-cells have demonstrated in-vitro and in-vivo anti-myeloma cell kill in mouse models, although expression of CS1 on CD8+ T-cells led to fratricide. 71 Several early phase clinical trials are assessing the maximum tolerated dose, safety, and efficacy of CS1 CAR T-cells in RRMM. The CARAMBA-1 trial (NCT04499339) is a first-in-human phase 1-2 study that manufactures SLAMF7 CAR T-cells using the virus-free Sleeping Beauty transposon system for gene-transfer.…”

Section: Non-bcma Targetsmentioning

confidence: 99%

CAR T-Cell Therapy for Patients with Multiple Myeloma: Current Evidence and Challenges

Rendo¹,

Joseph²,

Phan³

et al. 2022

BLCTT

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The therapeutic landscape of multiple myeloma (MM) has benefited from an emergence of novel therapies over the last decade. By inducing T-cell kill of target cancer cells, chimeric antigen receptor (CAR) T-cell therapies have improved outcomes of patients with hematologic malignancies. B-cell maturation antigen (BCMA) is the current target antigen of choice for most CAR T-cell products under investigation for MM. However, their shortcomings deal with logistical and clinical challenges, including limited availability, manufacturing times, and toxicities. This article provides an overview of recently developed and investigational CAR T-cell therapies for MM, highlighting current evidence and challenges.

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CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells

Cited by 29 publications

References 33 publications

Innovation in BCMA CAR-T therapy: Building beyond the Model T

Innovation in BCMA CAR-T therapy: Building beyond the Model T

Tumor buster - where will the CAR-T cell therapy ‘missile’ go?

CAR T-Cell Therapy for Patients with Multiple Myeloma: Current Evidence and Challenges

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