Anti-BCMA chimeric antigen receptors with fully human heavy-chain-only antigen recognition domains

Lam, Norris; Trinklein, Nathan D.; Buelow, Benjamin; Patterson, George H.; Ojha, Namrata; Kochenderfer, James N.

doi:10.1038/s41467-019-14119-9

Cited by 77 publications

(80 citation statements)

References 63 publications

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“…One of the first CAR T-cell products for treatment of MM incorporating a fully human anti-BCMA CAR was developed at MSKCC ( 76 ) and has recently been tested clinically as MCARH171 (NCT03070327). Another anti-BCMA CAR T-cell product with a fully human antigen binding domain is the FHVH-BCMA-T containing a heavy-chain-only antigen recognition domain ( 64 , 65 ). This product is currently under clinical evaluation at the NIH (NCT03602612).…”

Section: T-cell Directed Strategies To Improve Persistency Potency Amentioning

confidence: 99%

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

et al. 2020

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Despite recent therapeutic advances, the prognosis of multiple myeloma (MM) patients remains poor. Thus, new strategies to improve outcomes are imperative. Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape of B-cell malignancies, providing a potentially curative option for patients who are refractory to standard treatment. Long-term remissions achieved in patients with acute lymphoblastic leukemia and Non-Hodgkin Lymphoma encouraged its further development in MM. B-cell maturation antigen (BCMA)-targeted CAR T-cells have established outstanding results in heavily pre-treated patients. However, several other antigens such as SLAMF7 and CD44v6 are currently under investigation with promising results. Idecabtagene vicleucel is expected to be approved soon for clinical use. Unfortunately, relapses after CAR T-cell infusion have been reported. Hence, understanding the underlying mechanisms of resistance is essential to promote prevention strategies and to enhance CAR T-cell efficacy. In this review we provide an update of the most recent clinical and pre-clinical data and we elucidate both, the potential and the challenges of CAR T-cell therapy in the future.

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Section: T-cell Directed Strategies To Improve Persistency Potency Amentioning

confidence: 99%

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

et al. 2020

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“…In addition, the smaller size of this CAR is another advantage which may greatly reduce anti-CAR immune response (147). Obtained data revealed that, similar to conventional CAR T cells, after exposure to B-cell maturation antigen (BCMA) positive tumor cells, T cells expressing FHVH33-CD8BBZ can lyse tumor cells, produce cytokine and eradicate tumor cells in vivo (148).…”

Section: Blunting Host Immune Responsesmentioning

confidence: 99%

Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward

et al. 2020

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CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence. We also offer our viewpoint on how growing use of CAR T cells in various cancers may require modifications in the intrinsic and extrinsic survival signals of CAR T cells. We anticipate these amendments will additionally provide the rationales for generation of more persistent, and thereby, more effective CAR T cell treatments. CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence. We also offer our viewpoint on how growing use of CAR T cells in various cancers may require modifications in the intrinsic and extrinsic survival signals of CAR T cells. We anticipate these amendments will additionally provide the rationales for generation of more persistent, and thereby, more effective CAR T cell treatments.

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“…It is clear that a fully humanized CAR may reduce immune rejection compared to a murine-based CAR. In an attempt to reduce immune response even further, Lam and colleagues developed an anti-BCMA CAR carrying only a fully human heavy-chain variable domain instead of a complete scFv [ 115 ]. NSG mice were transplanted with MM.1S multiple myeloma cell line or with a human myeloma cell line.…”

Section: Preclinical Evaluation Of Car T and Car Nk Cell Therapiesmentioning

confidence: 99%

“…After establishing solid tumors, injection of anti-BCMA CAR T cells confirmed complete elimination of the tumors. Interestingly, long-term persistence and higher expansion of CAR T cells was only found in vivo when the CAR including only the heavy-chain of anti-BCMA scFv was combined with the 4-1BB co-stimulatory domain but not when including a CD28 co-stimulatory domain [ 115 ]. The same strategy was adapted for an anti-CD33 CAR for treatment of acute myeloid leukemia (AML) cells, which express high levels of the CD33 antigen [ 116 ].…”

Section: Preclinical Evaluation Of Car T and Car Nk Cell Therapiesmentioning

confidence: 99%

Humanized Mice Are Precious Tools for Preclinical Evaluation of CAR T and CAR NK Cell Therapies

Mhaidly

Verhoeyen

2020

Cancers

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Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for hematological malignancies. However, improvements in CAR T-cell therapies are urgently needed since CAR T cell application is associated with toxicities, exhaustion, immune suppression, lack of long-term persistence, and low CAR T-cell tumor infiltration. Major efforts to overcome these hurdles are currently on the way. Incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system and tumor tissue, represent an important fundamental and preclinical research tool. We will focus here on several CAR T and CAR NK therapies that have benefited from evaluation in humanized mice. These models are of great value for the cancer therapy field as they provide a more reliable understanding of sometimes complicated therapeutic interventions. Additionally, they are considered the gold standard with regard to assessment of new CAR technologies in vivo for safety, efficacy, immune response, design, combination therapies, exhaustion, persistence, and mechanism of action prior to starting a clinical trial. They help to expedite the critical translation from proof-of-concept to clinical CAR T-cell application. In this review, we discuss innovative developments in the CAR T-cell therapy field that benefited from evaluation in humanized mice, illustrated by multiple examples.

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Anti-BCMA chimeric antigen receptors with fully human heavy-chain-only antigen recognition domains

Cited by 77 publications

References 63 publications

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward

Humanized Mice Are Precious Tools for Preclinical Evaluation of CAR T and CAR NK Cell Therapies

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