美国哈佛医学院Mohammad Rashidian小组发现，CAR增强剂可提高CAR T细胞的活性和持久性。2024年7月30日，国际知名学术期刊《自然—生物技术》在线发表了这一成果。

为了延长嵌合抗原受体（CAR） T细胞的疗效，研究人员开发了一种CAR增强剂（CAR-E），其由一个CAR T细胞抗原与免疫调节分子融合而成。研究人员使用了B细胞成熟抗原（BCMA）CAR T细胞治疗多发性骨髓瘤，并将BCMA与低亲和力的白细胞介素2（IL-2）融合，形成CAR-E。这种策略在抗原-CAR结合时选择性地诱导CAR T细胞中的IL-2信号，从而增强T细胞的激活和抗肿瘤活性，同时减少IL-2相关的毒性。

研究人员展示了BCMA CAR-E选择性结合CAR T细胞，增加CAR T细胞的增殖、肿瘤细胞的清除以及记忆CAR T细胞的生成。这些记忆细胞在再刺激后保留重新扩增的能力，有效地控制了肿瘤的生长。机制研究揭示了CAR和IL-2受体内域在CAR-E作用机制中的作用。CAR-E方法避免了特定工程的需求，并使CAR T细胞治疗能够使用更低的细胞剂量。

据悉，虽然CAR T细胞治疗已显示出有前景的临床结果，但持久缓解仍然有限。

附：英文原文

Title: A CAR enhancer increases the activity and persistence of CAR T cells

Author: 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

Issue&Volume: 2024-07-30

Abstract: 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.

DOI: 10.1038/s41587-024-02339-4

Source: https://www.nature.com/articles/s41587-024-02339-4