Pei Y Teo, Youngrock Jung, David H Quach, Joanna Koh, Richard W Ong, Angeline Goh, Alrina Tan, Chee H Ng, Cheah C Seh, Kar W Tan, Ivan D Horak, Lionel Low
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引用次数: 0
Abstract
Allogeneic chimeric antigen receptor (CAR)-expressing T cells offer many advantages over autologous therapies, but their benefits are curtailed by graft-versus-host disease and elimination by recipient immune cells. Moreover, just as with autologous therapies, allogeneic CAR T cells are susceptible to activation-induced cell death (AICD) caused by chronic antigen exposure (CAE). Granzyme B- and Fas/Fas ligand-initiated caspase-mediated apoptoses are key mechanisms of T-cell death caused by T/NK cell-mediated allorejection or CAE. We explored a protective strategy of engineering CAR T cells to overexpress variants of the Granzyme B-specific serine protease inhibitor SERPINB9 (SB9) to improve allogeneic T-cell persistence and antitumor efficacy. We showed that the overexpression of an SB9 variant with broadened caspase specificity, SB9(CAS), not only significantly reduced rejection of allogeneic CAR T cells but also increased their resistance to AICD and enabled them to thrive better under CAE, thus improving allogeneic T-cell persistence and antitumor activity in vitro and in vivo. In addition, although SB9(CAS) overexpression improved the efficacy of allogeneic CAR T-cell therapy by conferring protection to cell death, we did not observe any autonomous growth, and the engineered CAR T cells were still susceptible to an inducible suicide switch. Hence, SB9(CAS) overexpression is a promising strategy that can strengthen current development of cell therapies, broadening their applications to address unmet medical needs.
与自体疗法相比,表达嵌合抗原受体(CAR)的异体 T 细胞具有许多优势,但它们的益处因移植物抗宿主疾病(GvHD)和受体免疫细胞的清除而受到限制。此外,与自体疗法一样,异体 CAR T 细胞也容易受到慢性抗原暴露(CAE)引起的活化诱导细胞死亡(AICD)的影响。颗粒酶 B(GzmB)和 Fas/FasL 引发、Caspase 介导的细胞凋亡是 T/NK 细胞介导的异体排斥或 CAE 导致 T 细胞死亡的关键机制。我们探索了一种保护性策略,即设计 CAR T 细胞,使其过度表达 GzmB 特异性丝氨酸蛋白酶抑制剂 SerpinB9(SB9)的变体,以提高异体 T 细胞的持久性和抗肿瘤疗效。我们的研究表明,过表达一种具有更广泛的caspase特异性的SB9变体SB9(CAS),不仅能显著降低异体CAR T细胞的排斥反应,还能增强它们对AICD的抵抗力,使它们在CAE下更好地生长,从而提高异体T细胞在体外和体内的持久性和抗肿瘤活性。此外,虽然SB9(CAS)外表达能保护细胞不死亡,从而提高异基因CAR T细胞疗法的疗效,但我们并没有观察到任何自主生长,而且工程化的CAR T细胞仍然易受诱导性自杀开关的影响。因此,SB9(CAS)外表达是一种很有前景的策略,它可以加强目前细胞疗法的发展,扩大其应用范围,以满足未得到满足的医疗需求。
期刊介绍:
Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes.
Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.