Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Pharmacology Program, Weill Cornell Medical College, New York, New York.
Cancer Immunol Res. 2024 Oct 1;12(10):1361-1379. doi: 10.1158/2326-6066.CIR-24-0246.
Chimeric antigen receptor (CAR) T-cell therapy has resulted in remarkable clinical success in the treatment of B-cell malignancies. However, its clinical efficacy in solid tumors is limited, primarily by target antigen heterogeneity. To overcome antigen heterogeneity, we developed CAR T cells that overexpress LIGHT, a ligand of both lymphotoxin-β receptor on cancer cells and herpes virus entry mediator on immune cells. LIGHT-expressing CAR T cells displayed both antigen-directed cytotoxicity mediated by the CAR and antigen-independent killing mediated through the interaction of LIGHT with lymphotoxin-β receptor on cancer cells. Moreover, CAR T cells expressing LIGHT had immunostimulatory properties that improved the cells' proliferation and cytolytic profile. These data indicate that LIGHT-expressing CAR T cells may provide a way to eliminate antigen-negative tumor cells to prevent antigen-negative disease relapse.
嵌合抗原受体 (CAR) T 细胞疗法在治疗 B 细胞恶性肿瘤方面取得了显著的临床成功。然而，其在实体瘤中的临床疗效有限，主要是由于靶抗原异质性。为了克服抗原异质性，我们开发了过表达 LIGHT 的 CAR T 细胞，LIGHT 是癌细胞上的淋巴毒素-β 受体和免疫细胞上的疱疹病毒进入介体的配体。表达 LIGHT 的 CAR T 细胞表现出两种作用：CAR 介导的抗原定向细胞毒性和通过 LIGHT 与癌细胞上的淋巴毒素-β 受体相互作用介导的抗原非依赖性杀伤。此外，表达 LIGHT 的 CAR T 细胞具有免疫刺激特性，可改善细胞的增殖和细胞溶解谱。这些数据表明，表达 LIGHT 的 CAR T 细胞可能提供了一种消除抗原阴性肿瘤细胞的方法，以防止抗原阴性疾病复发。
