A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors.
A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors.
复制标题
DOI：
10.1158/0008-5472.can-15-2524
复制
发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Moon EK
中科院分区：
文献类型：
--
作者：
Liu X;Ranganathan R;Jiang S;Fang C;Sun J;Kim S;Newick K;Lo A;June CH;Zhao Y;Moon EK
嵌合抗原受体（CAR）修饰过继t细胞疗法（ATC）已成功应用于血液系统恶性肿瘤的治疗，但在实体肿瘤治疗中仍面临许多挑战。一个主要的障碍是抑制受体（ir），即PD1在自然发生和基因修饰的肿瘤浸润淋巴细胞（TILs）中诱导的免疫抑制作用。我们假设干扰PD1信号会增强CAR - T细胞对抗实体肿瘤的活性。为了解决这种可能性，我们在CAR - t细胞中引入了一种基因工程开关受体结构，包括截断的PD1胞外结构域和CD28的跨膜和胞质信号域。我们测试了这种补充“PD1CD28”对人CAR - t细胞靶向表达相关肿瘤抗原的侵袭性人实体瘤模型的影响。与单独使用CAR - t细胞或PD1抗体治疗相比，用PD1CD28 CAR - t细胞治疗患有大的、已建立的实体瘤的小鼠，由于CAR - TIL浸润增强，肿瘤诱导功能减退的易感性降低，肿瘤体积显著缩小，IR表达减弱。综上所述，我们的研究结果表明，应用PD1CD28增强CAR - t细胞活性通过多种机制对实体肿瘤有效，促使对这种潜在的有前景的治疗方式进行临床研究。
Chimeric antigen receptor (CAR)-modified adoptive T-cell therapy (ATC) has been successfully applied to the treatment of hematologic malignancies, but faces many challenges in solid tumors. One major obstacle is the immune-suppressive effects induced in both naturally-occurring and genetically-modified tumor infiltrating lymphocytes (TILs) by inhibitory receptors (IRs), namely PD1. We hypothesized that interfering with PD1 signaling would augment CAR T cell activity against solid tumors. To address this possibility, we introduced a genetically-engineered switch receptor construct, comprising the truncated extracellular domain of PD1 and the transmembrane and cytoplasmic signaling domains of CD28, into CAR T-cells. We tested the effect of this supplement, “PD1CD28”, on human CAR T-cells targeting aggressive models of human solid tumors expressing relevant tumor antigens. Treatment of mice bearing large, established solid tumors with PD1CD28 CAR T-cells led to significant regression in tumor volume due to enhanced CAR TIL infiltrate, decreased susceptibility to tumor-induced hypofunction, and attenuation of IR expression compared to treatments with CAR T-cells alone or PD1 antibodies. Taken together, our findings suggest that the application of PD1CD28 to boost CAR T-cell activity is efficacious against solid tumors via a variety of mechanisms, prompting clinical investigation of this potentially promising treatment modality.