Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18–secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.

中文翻译：

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分泌 IL-18 的多抗原靶向 CAR T 细胞消除免疫活性小鼠模型中的低抗原骨髓瘤


多发性骨髓瘤是一种浆细胞恶性肿瘤，目前常规疗法无法治愈。继靶向 CD19 的嵌合抗原受体 (CAR) T 细胞在白血病和淋巴瘤中取得成功之后，靶向 B 细胞成熟抗原 (BCMA) 的 CAR T 细胞最近在复发性和难治性骨髓瘤患者中表现出令人印象深刻的活性。然而，由于骨髓瘤细胞上 BCMA 表达较弱，BCMA 导向的治疗可能会失败，这表明更好地解决这种低抗原疾病的新方法可能会改善患者的预后。我们假设促炎细胞因子白介素 18 (IL-18) 的工程化分泌和多抗原靶向可以提高 CAR T 细胞对抗 BCMA 低骨髓瘤的活性。在同基因小鼠骨髓瘤模型中，当这些抗原微弱表达时，靶向骨髓瘤相关抗原 BCMA 和 B 细胞激活因子受体 (BAFF-R) 的 CAR T 细胞无法消除骨髓瘤，而分泌 IL-18 的 CAR T 细胞则无法消除骨髓瘤。针对这些抗原促进了骨髓瘤的清除。分泌IL-18的CAR T细胞形成效应样T细胞表型，促进干扰素γ产生，通过I/II型干扰素信号重新编程骨髓瘤骨髓微环境，并激活巨噬细胞介导抗骨髓瘤活性。双 CAR T 细胞同时靶向弱表达的 BCMA 和 BAFF-R 增强了 T 细胞：靶细胞的亲和力，增加了整体 CAR 信号强度，并刺激了抗骨髓瘤活性。双抗原靶向增强了 CAR T 细胞对工程化 IL-18 的分泌，并有助于消除体内较大的骨髓瘤负担。 我们的结果表明，工程化 IL-18 分泌和多抗原靶向相结合可以通过不同的机制消除抗原表达较弱的骨髓瘤。