Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer.

Significance: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. Cancer Discov; 7(11); 1238–47. ©2017 AACR.

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成功的过继性T细胞免疫疗法对实体瘤的治疗将需要改善肿瘤内针对肿瘤的T细胞的扩增和细胞毒性。提供重组或转基因细胞因子可能产生所需的益处，但与明显的毒性相关，从而限制了临床应用。为了规避此限制，我们构建了组成型信号传导细胞因子受体C7R，该受体有效触发IL7信号传导轴，但对细胞外细胞因子无反应。抗原暴露后，该策略可增强修饰的T细胞功能，但避免刺激旁观者淋巴细胞。与肿瘤定向的嵌合抗原受体（CAR）共表达C7R在重复暴露于肿瘤细胞的过程中增加了T细胞增殖，存活和抗肿瘤活性，而没有T细胞功能障碍或自主性T细胞生长。此外，即使在没有C7R支持的情况下无效的细胞剂量下，共表达C7R的CAR T细胞对转移性神经母细胞瘤和原位胶质母细胞瘤异种移植模型也具有活性。因此，C7R可能能够增强针对癌症的抗原特异性T细胞疗法。

意义：此处开发的组成性信号转导C7R系统可对CAR T细胞产生有效的IL7刺激，从而提高其对多种临床前肿瘤模型的持久性和抗肿瘤活性，从而支持其临床开发。巨蟹座Discov; 7（11）；1238–47。©2017 AACR。

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