T-cell receptor (TCR)–modified T-cell gene therapy can target a variety of extracellular and intracellular tumor-associated antigens, yet has had little clinical success. A potential explanation for limited antitumor efficacy is a lack of T-cell activation in vivo . We postulated that expression of proinflammatory cytokines in TCR-modified T cells would activate T cells and enhance antitumor efficacy. We demonstrate that expression of interleukin 18 (IL18) in tumor-directed TCR-modified T cells provides a superior proinflammatory signal than expression of interleukin 12 (IL12). Tumor-targeted T cells secreting IL18 promote persistent and functional effector T cells and a proinflammatory tumor microenvironment. Together, these effects augmented overall survival of mice in the pmel-1 syngeneic tumor model. When combined with sublethal irradiation, IL18-secreting pmel-1 T cells were able to eradicate tumors, whereas IL12-secreting pmel-1 T cells caused toxicity in mice through excessive cytokine secretion. In another xenograft tumor model, IL18 secretion enhanced the persistence and antitumor efficacy of NY-ESO-1–reactive TCR-modified human T cells as well as overall survival of tumor-bearing mice. These results demonstrate a rationale for optimizing the efficacy of TCR-modified T-cell cancer therapy through expression of IL18. See related commentary by Wijewarnasuriya et al., [p. 732][1] [1]: /lookup/volpage/8/732?iss=6

中文翻译：

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T细胞受体修饰的T细胞用于癌症治疗的优化。

T细胞受体（TCR）修饰的T细胞基因疗法可靶向多种细胞外和细胞内肿瘤相关抗原，但临床成功率很小。有限的抗肿瘤功效的潜在解释是体内缺乏T细胞活化。我们推测在TCR修饰的T细胞中促炎细胞因子的表达将激活T细胞并增强抗肿瘤功效。我们证明白介素18（IL18）在肿瘤定向TCR修饰的T细胞中的表达提供了比白介素12（IL12）的表达优越的促炎信号。分泌IL18的靶向肿瘤的T细胞可促进持久性和功能性效应T细胞和促炎性肿瘤微环境。这些作用共同提高了pmel-1同基因肿瘤模型中小鼠的整体存活率。当结合亚致死辐射时，分泌IL18的pmel-1 T细胞能够根除肿瘤，而分泌IL12的pmel-1 T细胞通过细胞因子分泌过多而对小鼠产生毒性。在另一个异种移植肿瘤模型中，IL18分泌增强了NY-ESO-1反应性TCR修饰的人类T细胞的持久性和抗肿瘤功效，以及荷瘤小鼠的整体存活率。这些结果证明了通过表达IL18来优化TCR修饰的T细胞癌症疗法的功效的原理。参见Wijewarnasuriya等人的相关评论，[p。732] [1] [1]：/ lookup / volpage / 8/732？iss = 6 IL18分泌增强了NY-ESO-1反应性TCR修饰的人类T细胞的持久性和抗肿瘤功效，以及荷瘤小鼠的整体存活率。这些结果证明了通过表达IL18来优化TCR修饰的T细胞癌症疗法的功效的原理。参见Wijewarnasuriya等人的相关评论，[p。732] [1] [1]：/ lookup / volpage / 8/732？iss = 6 IL18分泌增强了NY-ESO-1反应性TCR修饰的人类T细胞的持久性和抗肿瘤功效，以及荷瘤小鼠的整体存活率。这些结果证明了通过表达IL18来优化TCR修饰的T细胞癌症疗法的功效的原理。参见Wijewarnasuriya等人的相关评论，[p。732] [1] [1]：/ lookup / volpage / 8/732？iss = 6