Individualized in situ vaccination by radiation and immunotherapy

 描述(由申请人提供)：最近免疫治疗的成功证明了T细胞排斥肿瘤的能力。从临床研究中发现了两个关键观察结果。首先，一些转移性疾病患者有足够数量和数量的肿瘤反应性T细胞，可以通过免疫检查点抑制剂释放出来，导致肿瘤消退。其次，单个肿瘤表达的独特突变蛋白是强大的肿瘤特异性T细胞抗原的未开发来源。由于大多数癌症患者缺乏显著的抗肿瘤免疫反应，并且对目前可用的免疫疗法没有反应，因此迫切需要设计新的策略来为这些患者接种针对他们个人肿瘤的疫苗。我们在探索局部肿瘤放射治疗(RT)作为一种在免疫原性背景下释放肿瘤抗原的手段方面进行了开创性的研究。我们是第一个证明RT将不敏感的小鼠肿瘤转化为对CTLA-4阻断有反应的肿瘤，最近完成了一项针对肺癌的前瞻性临床试验，肺癌是一种对抗CTLA-4单一治疗没有反应的肿瘤类型。中期分析显示，这一组合具有令人鼓舞的活动，并有一些完全和部分反应。重要的是，我们已经证明，通过RT启动针对内源性肿瘤抗原的CD8T细胞需要免疫检查点阻断。我们的初步数据还表明，RT+CTLA-4阻断可引起肿瘤内CD8 T细胞T细胞受体(TCR)的独特变化。在有反应的患者的外周血中也发现了TCR谱的显著变化。因此，我们发表的初步数据有力地支持了这样的假设，即RT可以产生有效的个性化原位肿瘤疫苗。然而，一些悬而未决的问题阻碍了RT作为一种广泛可用且相对便宜的靶向患者特异性新抗原谱系的策略的快速进展。例如，缺乏RT诱导T细胞对新抗原的反应的证据，并且尚不清楚RT是否通过改变存活的受辐射的癌细胞的转录组来暴露在未经治疗的肿瘤中未表达的独特的新抗原。RT方案和免疫检查点抑制剂对这一过程的影响仍然知之甚少。最后，虽然有证据表明异常效应是由T细胞介导的，但这些T细胞反应的特异性尚未得到表征。提出的研究旨在回答这些问题，以推动该领域的发展，并改进临床试验设计和RT与免疫治疗的结合使用。将对RT联合抗CTLA-4或抗PD-1激活的T细胞的特异性进行全面评估。此外，我们还将描述RT对肿瘤突变组的影响，以确定RT可能暴露的免疫原性突变。对接受RT+抗CTLA-4治疗的患者的样本进行分析将提供初步的人类证据。

 DESCRIPTION (provided by applicant): Recent successes of immunotherapy have demonstrated the power of T cells to reject tumors. Two key observations have emerged from clinical studies. First, some patients with metastatic disease have a sufficient number and repertoire of tumor-reactive T cells that can be unleashed by immune checkpoint inhibitors to cause tumor regression. Second, unique mutated proteins expressed by an individual tumor are an untapped source of powerful tumor-specific T cell antigens. Because most cancer patients lack significant anti-tumor immune responses and do not respond to currently available immunotherapies, there is an urgent need to devise novel strategies to vaccinate these patients against their own individual tumor. We have pioneered studies to explore the use of local tumor radiotherapy (RT) as a means to release tumor antigens in an immunogenic context. We were the first to demonstrate that RT converted an insensitive mouse carcinoma into one responsive to CTLA-4 blockade, and have recently completed a prospective clinical trial testing this combination in lung cancer, a tumor type unresponsive to anti-CTLA-4 monotherapy. Interim analysis shows encouraging activity of the combination, with some complete and partial responses. Importantly, we have shown that priming of CD8 T cells specific for endogenous tumor antigens by RT requires immune checkpoint blockade. Our preliminary data also indicate that unique changes in T cell receptor (TCR) repertoire of intra-tumoral CD8 T cells are induced by RT + CTLA-4 blockade. Significant changes in TCR repertoire were also seen in peripheral blood of responding patients. Thus, our published and preliminary data strongly support the hypothesis that RT can generate an effective individualized in situ tumor vaccine. However, several unanswered questions hinder rapid progress in the use of RT as a widely available and relatively inexpensive strategy to target the patient-specific neoantigen repertoir. For instance, evidence that RT induces T cell responses to neoantigens is lacking, and it is not known if by changing the transcriptome of surviving irradiated cancer cells RT may expose unique neoantigens not expressed in untreated tumors. The influence of the RT regimen and of the immune checkpoint inhibitor used on this process remain poorly understood. Finally, while there is evidence that abscopal effects are mediated by T cells, the specificity of these T cell responses has not been characterized. Studies proposed are aimed at answering these questions in order to move the field forward and improve clinical trial design and the use of RT in combination with immunotherapy. A comprehensive evaluation of the specificity of T cells activated by RT combined with anti-CTLA-4 or anti-PD-1 will be performed. In addition, we will characterize the effects of RT on the tumor mutanome to identify potential immunogenic mutations exposed by RT. Analysis of samples from patients treated with RT+anti-CTLA-4 will provide preliminary evidence in humans.