Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
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DOI：
10.1158/1078-0432.ccr-17-1788
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发表时间：
2018-08-15
影响因子：
11.5
通讯作者：
Petrausch, Ulf
中科院分区：
文献类型：
--
作者：
Gulati, Pratiksha;Ruhl, Julia;Petrausch, Ulf
目的：过继转移的重定向T细胞和检查点抑制剂的联合治疗旨在提高对免疫治疗反应不良的肿瘤（如恶性胸膜间皮瘤（MPM））的反应率。实验设计：建立了具有不同共刺激结构域的成纤维细胞活化蛋白（FAP）特异性汽车，所述共刺激结构域包括CD 28、Delta-CD 28（缺乏lck结合部分）或4-1BB。在体外表征了CAR-T细胞，并在人源化小鼠模型中与PD-1阻断联合体内测试了抗肿瘤功效。最后，Delta-CD 28 CAR在MPM患者中进行临床测试。结果：所有三种汽车在体外均显示FAP特异性功能。基因表达数据表明Delta-CD 28 CAR的独特活性谱，包括参与细胞分裂、糖酵解、脂肪酸氧化和氧化磷酸化的基因的较高表达。在体内，仅表达Delta-CD 28 CAR的T细胞与PD-1阻断剂组合控制肿瘤生长。当注射到MPM患者的胸腔积液中时，Delta-CD 28 CAR可以检测到长达21天并显示functional.Conclusions：总体而言，抗FAP-Delta-CD 28/CD 3 zeta CAR T细胞显示出上级的体外功能，在人源化小鼠中与PD-1阻断组合时更好的肿瘤控制，并且在MPM患者中持续长达21天。因此，有必要对这种优化的CAR进行进一步的临床研究。(C)2018年AACR。
Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Delta-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Delta-CD28 CAR was tested clinically in a patient with MPM.Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the Delta-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Delta-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Delta-CD28 CAR could be detected for up to 21 days and showed functionality.Conclusions: Overall, anti-FAP-Delta-CD28/CD3 zeta CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. (C) 2018 AACR.