Rakhshandehroo Taha, Mantri Shreya R, Moravej Heydar, Louis Benjamin B V, Salehi Farid Ali, Munaretto Leila, Regan Kathryn, Khan Radia M M, Wolff Alexandra, Farkash Zoe, Cong Min, Kuhnast Adrien, Nili Ali, Lee Uk-Jae, Allen Harris H, Berland Lea, Simkova Ester, Uslu Safak C, Tavakolpour Soheil, Rowley Jennifer E, Codet Elisabeth, Shahbazian Haneyeh, Baral Jessika, Pyrdol Jason, Jacobson Caron A, Nadeem Omar, Nia Hadi T, Wucherpfennig Kai W, Rashidian Mohammad
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Biomedical Engineering, Boston University, Boston, MA, USA.
Nat Biotechnol. 2024 Jul 30. doi: 10.1038/s41587-024-02339-4.
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.
尽管嵌合抗原受体（CAR）T细胞疗法已展现出颇具前景的临床疗效，但持久缓解仍较为有限。为了延长CAR T细胞的疗效，我们开发了一种CAR增强剂（CAR-E），它由与免疫调节分子融合的CAR T细胞抗原组成。在此，我们展示了使用靶向B细胞成熟抗原（BCMA）的CAR T细胞治疗多发性骨髓瘤的这一策略，所使用的CAR-E由与低亲和力白细胞介素2（IL-2）融合的BCMA组成。这在抗原与CAR结合后能选择性地在CAR T细胞中诱导IL-2信号传导，增强T细胞活化和抗肿瘤活性，同时降低与IL-2相关的毒性。我们表明，BCMA CAR-E能选择性地结合CAR T细胞，并增加CAR T细胞增殖、肿瘤细胞清除以及记忆性CAR T细胞的产生。记忆细胞在再次刺激时保留重新扩增的能力，在再次攻击时能有效控制肿瘤生长。机制研究揭示了CAR和IL-2受体内结构域均参与了CAR-E的作用机制。CAR-E方法无需特定工程改造，且能以更低的细胞剂量进行CAR T细胞治疗。
