Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Blood Cancer Discov. 2022 Mar 1;3(2):136-153. doi: 10.1158/2643-3230.BCD-21-0181.
Chimeric antigen receptor (CAR) T cells induce impressive responses in patients with hematologic malignancies but can also trigger cytokine release syndrome (CRS), a systemic toxicity caused by activated CAR T cells and innate immune cells. Although IFNγ production serves as a potency assay for CAR T cells, its biologic role in conferring responses in hematologic malignancies is not established. Here we show that pharmacologic blockade or genetic knockout of IFNγ reduced immune checkpoint protein expression with no detrimental effect on antitumor efficacy against hematologic malignancies in vitro or in vivo. Furthermore, IFNγ blockade reduced macrophage activation to a greater extent than currently used cytokine antagonists in immune cells from healthy donors and serum from patients with CAR T-cell-treated lymphoma who developed CRS. Collectively, these data show that IFNγ is not required for CAR T-cell efficacy against hematologic malignancies, and blocking IFNγ could simultaneously mitigate cytokine-related toxicities while preserving persistence and antitumor efficacy.
Blocking IFNγ in CAR T cells does not impair their cytotoxicity against hematologic tumor cells and paradoxically enhances their proliferation and reduces macrophage-mediated cytokines and chemokines associated with CRS. These findings suggest that IFNγ blockade may improve CAR T-cell function while reducing treatment-related toxicity in hematologic malignancies. See related content by McNerney et al., p. 90 (17). This article is highlighted in the In This Issue feature, p. 85.
嵌合抗原受体 (CAR) T 细胞在血液系统恶性肿瘤患者中引起显著的反应，但也可引发细胞因子释放综合征 (CRS)，这是由激活的 CAR T 细胞和先天免疫细胞引起的全身性毒性。虽然 IFNγ 的产生可作为 CAR T 细胞的效力测定，但它在赋予血液系统恶性肿瘤反应中的生物学作用尚未确定。在这里，我们表明，药理阻断或 IFNγ 的基因敲除减少了免疫检查点蛋白的表达，对 CAR T 细胞治疗淋巴瘤患者发生 CRS 的体外或体内血液系统恶性肿瘤的抗肿瘤疗效没有不利影响。此外，IFNγ 阻断在健康供体的免疫细胞和接受 CAR T 细胞治疗的淋巴瘤患者的血清中比目前使用的细胞因子拮抗剂更能减少巨噬细胞的激活。总之，这些数据表明，IFNγ 对于 CAR T 细胞对抗血液系统恶性肿瘤的疗效不是必需的，并且阻断 IFNγ 可以同时减轻细胞因子相关毒性，同时保持持久性和抗肿瘤疗效。
在 CAR T 细胞中阻断 IFNγ 不会损害其对血液系统肿瘤细胞的细胞毒性，反而会增强其增殖，并减少与 CRS 相关的巨噬细胞介导的细胞因子和趋化因子。这些发现表明，IFNγ 阻断可能会改善 CAR T 细胞功能，同时降低血液系统恶性肿瘤的治疗相关毒性。请参阅 McNerney 等人在本期特色栏目中，第 90 页的相关内容（17）。本文在本期焦点栏目中，第 85 页进行了重点介绍。
