尽管嵌合抗原受体 (CAR) T 细胞疗法已展现出良好的临床效果，但持久缓解仍然有限。为了扩展 CAR T 细胞的功效，我们开发了一种 CAR 增强剂 (CAR-E)，其中包含与免疫调节分子融合的 CAR T 细胞抗原。在这里，我们展示了使用 B 细胞成熟抗原 (BCMA) CAR T 细胞治疗多发性骨髓瘤的策略，其中 CAR-E 由 BCMA 与低亲和力白细胞介素 2 (IL-2) 融合组成。当抗原与 CAR 结合时，这会选择性诱导 CAR T 细胞中的 IL-2 信号传导，增强 T 细胞活化和抗肿瘤活性，同时减少 IL-2 相关的毒性。我们表明，BCMA CAR-E 选择性结合 CAR T 细胞，并增加 CAR T 细胞增殖、肿瘤细胞清除和记忆 CAR T 细胞的发育。记忆细胞保留了在再刺激时重新扩张的能力，从而在再次攻击时有效控制肿瘤生长。机制研究揭示了 CAR 和 IL-2 受体胞内结构域参与 CAR-E 的作用机制。 CAR-E 方法避免了对特定工程的需要，并能够以较低的细胞剂量进行 CAR T 细胞治疗。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

Although chimeric antigen receptor (CAR) T cell therapies have demonstrated promising clinical outcomes, durable remissions remain limited. To extend the efficacy of CAR T cells, we develop a CAR enhancer (CAR-E), comprising a CAR T cell antigen fused to an immunomodulatory molecule. Here we demonstrate this strategy using B cell maturation antigen (BCMA) CAR T cells for the treatment of multiple myeloma, with a CAR-E consisting of the BCMA fused to a low-affinity interleukin 2 (IL-2). This selectively induces IL-2 signaling in CAR T cells upon antigen-CAR binding, enhancing T cell activation and antitumor activity while reducing IL-2-associated toxicities. We show that the BCMA CAR-E selectively binds CAR T cells and increases CAR T cell proliferation, clearance of tumor cells and development of memory CAR T cells. The memory cells retain the ability to re-expand upon restimulation, effectively controlling tumor growth upon rechallenge. Mechanistic studies reveal the involvement of both CAR and IL-2 receptor endodomains in the CAR-E mechanism of action. The CAR-E approach avoids the need for specific engineering and enables CAR T cell therapy with lower cell doses.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.