The IAP antagonist birinapant enhances chimeric antigen receptor T cell therapy for glioblastoma by overcoming antigen heterogeneity.

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy Oncolytics Pub Date : 2022-11-15 eCollection Date: 2022-12-15 DOI:10.1016/j.omto.2022.11.004
Edward Z Song, Xin Wang, Benjamin I Philipson, Qian Zhang, Radhika Thokala, Logan Zhang, Charles-Antoine Assenmacher, Zev A Binder, Guo-Li Ming, Donald M O'Rourke, Hongjun Song, Michael C Milone
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Abstract

Antigen heterogeneity that results in tumor antigenic escape is one of the major obstacles to successful chimeric antigen receptor (CAR) T cell therapies in solid tumors including glioblastoma multiforme (GBM). To address this issue and improve the efficacy of CAR T cell therapy for GBM, we developed an approach that combines CAR T cells with inhibitor of apoptosis protein (IAP) antagonists, a new class of small molecules that mediate the degradation of IAPs, to treat GBM. Here, we demonstrated that the IAP antagonist birinapant could sensitize GBM cell lines and patient-derived primary GBM organoids to apoptosis induced by CAR T cell-derived cytokines, such as tumor necrosis factor. Therefore, birinapant could enhance CAR T cell-mediated bystander death of antigen-negative GBM cells, thus preventing tumor antigenic escape in antigen-heterogeneous tumor models in vitro and in vivo. In addition, birinapant could promote the activation of NF-κB signaling pathways in antigen-stimulated CAR T cells, and with a birinapant-resistant tumor model we showed that birinapant had no deleterious effect on CAR T cell functions in vitro and in vivo. Overall, we demonstrated the potential of combining the IAP antagonist birinapant with CAR T cells as a novel and feasible approach to overcoming tumor antigen heterogeneity and enhancing CAR T cell therapy for GBM.

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IAP拮抗剂比瑞那潘通过克服抗原异质性增强了治疗胶质母细胞瘤的嵌合抗原受体T细胞疗法。
导致肿瘤抗原逃避的抗原异质性是嵌合抗原受体(CAR)T细胞疗法成功治疗包括多形性胶质母细胞瘤(GBM)在内的实体瘤的主要障碍之一。为了解决这一问题并提高CAR T细胞疗法治疗GBM的疗效,我们开发了一种方法,将CAR T细胞与凋亡蛋白抑制剂(IAP)拮抗剂(一种介导IAP降解的新型小分子)结合起来治疗GBM。在这里,我们证明了 IAP 拮抗剂 birinapant 可使 GBM 细胞系和源自患者的原发性 GBM 器官组织对 CAR T 细胞衍生的细胞因子(如肿瘤坏死因子)诱导的细胞凋亡敏感。因此,birinapant 可以增强 CAR T 细胞介导的抗原阴性 GBM 细胞的旁观者死亡,从而防止抗原异质性肿瘤模型在体外和体内的肿瘤抗原逃逸。此外,比瑞那潘还能促进抗原刺激的 CAR T 细胞中 NF-κB 信号通路的活化,而且通过比瑞那潘耐药的肿瘤模型,我们发现比瑞那潘对体外和体内的 CAR T 细胞功能没有有害影响。总之,我们证明了 IAP 拮抗剂 birinapant 与 CAR T 细胞结合的潜力,这是克服肿瘤抗原异质性和增强 CAR T 细胞治疗 GBM 的一种新颖可行的方法。
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来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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