Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells.
Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells.
复制标题
DOI：
10.1158/2159-8290.cd-17-0538
复制
发表时间：
2017-11
期刊：
影响因子：
28.2
通讯作者：
Rooney CM
中科院分区：
文献类型：
--
作者：
Shum T;Omer B;Tashiro H;Kruse RL;Wagner DL;Parikh K;Yi Z;Sauer T;Liu D;Parihar R;Castillo P;Liu H;Brenner MK;Metelitsa LS;Gottschalk S;Rooney CM
实体瘤的成功过继性T细胞免疫疗法将需要肿瘤内肿瘤定向T细胞的改善的扩增和细胞毒性。提供重组或转基因细胞因子可以产生期望的益处，但与显著的毒性相关，限制了临床使用。为了规避这一限制，我们构建了一个组成型信号细胞因子受体，C7 R，它有效地触发IL-7信号轴，但对细胞外细胞因子无反应。这种策略增强了抗原暴露后修饰的T细胞功能，但避免刺激旁观者淋巴细胞。在重复暴露于肿瘤细胞期间，C7 R与肿瘤定向嵌合抗原受体（CAR）共表达增加了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T细胞生长。此外，C7 R共表达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具有活性，即使在没有C7 R支持的情况下无效的细胞剂量下也是如此。因此，C7 R可能能够增强针对癌症的抗原特异性T细胞疗法。
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 are associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL-7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Co-expressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and anti-tumor activity during repeated exposure to tumor cells, without T cell dysfunction or autonomous T cell growth. Furthermore, C7R co-expressing 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.