CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation

Lin, Zigen; Tang, Xiaozhu; Cao, Yuhao; Yang, Li-Jin; Jiang, Mingmei; Li, Xinying; Min, Jie; Chen, Bing; Yang, Ye; Gu, Chunyan

doi:10.18632/aging.204405

Cited by 2 publications

(1 citation statement)

References 51 publications

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“…Although this is a logical consequence of increasing the antigen density threshold through reduction of CAR affinity, careful consideration of the probability of immune escape through this mechanism is essential. In the case of MM, CD229 has been shown to be highly and homogeneously expressed within individual tumor samples (17)(18)(19)(20)43), and CD229 function appears important to maintain the malignant phenotype (17,44). These observations suggest that the emergence of CD229 low MM cells may be unlikely, but clinical trials will be necessary to ultimately answer this question.…”

Section: Discussionmentioning

confidence: 99%

Systematic single amino acid affinity tuning of CD229 CAR T cells retains efficacy against multiple myeloma and eliminates on-target off-tumor toxicity

Vander Mause,

Baker,

Dietze

et al. 2023

Sci. Transl. Med.

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T cells expressing chimeric antigen receptors (CARs) have shown remarkable therapeutic activity against different types of cancer. However, the wider use of CAR T cells has been hindered by the potential for life-threatening toxicities due to on-target off-tumor killing of cells expressing low amounts of the target antigen. CD229, a signaling lymphocyte-activation molecule (SLAM) family member, has previously been identified as a target for CAR T cell–mediated treatment of multiple myeloma (MM) due to its high expression on the surfaces of MM cells. CD229 CAR T cells have shown effective clearance of MM cells in vitro and in vivo. However, healthy lymphocytes also express CD229, albeit at lower amounts than MM cells, causing their unintended targeting by CD229 CAR T cells. To increase the selectivity of CD229 CAR T cells for MM cells, we used a single amino acid substitution approach of the CAR binding domain to reduce CAR affinity. To identify CARs with increased selectivity, we screened variant binding domains using solid-phase binding assays and biolayer interferometry and determined the cytotoxic activity of variant CAR T cells against MM cells and healthy lymphocytes. We identified a CD229 CAR binding domain with micromolar affinity that, when combined with overexpression of c-Jun, confers antitumor activity comparable to parental CD229 CAR T cells but lacks the parental cells’ cytotoxic activity toward healthy lymphocytes in vitro and in vivo. The results represent a promising strategy to improve the efficacy and safety of CAR T cell therapy that requires clinical validation.

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