Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.
Sci Rep. 2017 Sep 5;7(1):10541. doi: 10.1038/s41598-017-10940-8.
Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy for the management of solid tumor malignancies. In ovarian cancer, this is in part due to an immunosuppressive cytokine and cellular tumor microenvironment which suppresses adoptively transferred T cells. We engineered an armored CAR T cell capable of constitutive secretion of IL-12, and delineate the mechanisms via which these CAR T cells overcome a hostile tumor microenvironment. In this report, we demonstrate enhanced proliferation, decreased apoptosis and increased cytotoxicity in the presence of immunosuppressive ascites. In vivo, we show enhanced expansion and CAR T cell antitumor efficacy, culminating in improvement in survival in a syngeneic model of ovarian peritoneal carcinomatosis. Armored CAR T cells mediated depletion of tumor associated macrophages and resisted endogenous PD-L1-induced inhibition. These findings highlight the role of the inhibitory microenvironment and how CAR T cells can be further engineered to maintain efficacy.
嵌合抗原受体 (CAR) T 细胞疗法在实体肿瘤恶性肿瘤的治疗中疗效有限。在卵巢癌中，部分原因是免疫抑制细胞因子和细胞肿瘤微环境抑制了过继转移的 T 细胞。我们设计了一种能够持续分泌 IL-12 的装甲 CAR T 细胞，并阐明了这些 CAR T 细胞克服恶劣肿瘤微环境的机制。在本报告中，我们证明了在存在免疫抑制性腹水的情况下，CAR T 细胞的增殖增强、凋亡减少和细胞毒性增加。在体内，我们显示了增强的扩张和 CAR T 细胞抗肿瘤疗效，最终在卵巢腹膜癌病的同种异体模型中改善了生存。装甲 CAR T 细胞介导的肿瘤相关巨噬细胞耗竭，并抵抗内源性 PD-L1 诱导的抑制。这些发现强调了抑制性微环境的作用以及如何进一步设计 CAR T 细胞以保持疗效。
