Induction of autosis to overcome resistance in adoptive cell therapy for solid tumors

项目摘要 过继细胞疗法是治疗癌症的一种很有前途的方法，但尽管付出了巨大的努力，临床结果 用肿瘤特异性T细胞表达T细胞受体(TCR)或T细胞受体(TCR)的ACT治疗实体瘤 嵌合抗原受体(CAR)没有表现出理想的治疗反应。最近，我们 开发了携带粘液瘤病毒的肿瘤特异性T细胞，以克服实体瘤ACT中的耐药性。我们 假设这些T细胞的抗实体肿瘤活性主要归因于一种特殊类型的肿瘤细胞 死亡，自体，以前没有被认为是T细胞杀伤机制，但可能有助于 通过靶向抗原阳性和抗原阴性的肿瘤细胞观察到令人兴奋的抗肿瘤效力。目标1 将确定肿瘤细胞自体的独特分子机制，这些机制是由 粘液瘤病毒衍生因子(S)和T细胞衍生可溶性因子(S)。目标2将决定这些因素的作用 肿瘤特异性T细胞在促进自体和强大的宿主免疫以根除实体瘤时 仅有约25%的肿瘤细胞表达靶向抗原。我们提议的研究将确定一种新的ACT 该策略具有消除具有很高抗原异质性的实体瘤的能力。这 翻译相关工作有望显著提高固体ACT的治疗指数 并可能为未来的临床试验奠定基础。

Project Summary Adoptive cell therapy is a promising approach to treat cancer, but despite tremendous efforts, results of clinical trials in human solid tumors using ACT with tumor-specific T cells expressing T-cell-receptors (TCR) or chimeric antigen receptors (CAR) have not demonstrated the desired therapeutic responses. Recently, we developed tumor-specific T cells loaded with the myxoma virus to overcome resistance in solid tumor ACT. We hypothesize that anti-solid tumor activity of these T cells is mainly attributed to a special type of tumor cell death, autosis, that has not been considered a T cell killing mechanism before but may contribute to the observed exciting antitumor potency by targeting both antigen-positive and antigen-negative tumor cells. Aim 1 will determine the unique molecular mechanism underlying tumor cell autosis induced by the synergy of myxoma virus-derived factor(s) with T cell-derived soluble factor(s). Aim 2 will determine the role of these tumor-specific T cells in promoting autosis and robust host immunity to eradicate solid tumors when the targeted antigen is expressed by only ~25% of tumor cells. Our proposed studies will identify a novel ACT strategy endowed with the capacity to eliminate solid tumors with very high antigen heterogeneity. This translationally relevant work holds promise to significantly advance the therapeutic index of ACT in solid tumors and could then lay the foundation for future clinical trials.