Identification and cloning of neoantigen-specific T cells for GBM immunotherapy

摘要/摘要 缺乏有效的胶质母细胞瘤治疗是一个重大的健康问题，并突显了创新的必要性 和创新的方法。免疫治疗是一种吸引人的策略，因为它具有潜在的免疫能力。 以运输细胞并摧毁大脑中浸润性肿瘤细胞。新的信息表明，患者人数不断增加 免疫治疗后的免疫反应优先识别肿瘤特异性产生的新抗原 突变。我们的数据，以及来自癌症患者其他免疫治疗策略的数据表明， 通过这种个性化的、患者特异性的免疫疗法诱导的绝大多数肿瘤特异性T细胞 不识别具有良好特性的已知抗原。这些信息与最近来自 其他免疫反应性癌症，如黑色素瘤，其中肿瘤特异性T细胞的百分比 识别已知抗原的比例不到1%。为了设计出最有效的免疫疗法 对于胶质母细胞瘤的治疗策略，我们认为了解哪些抗原是肿瘤特异性T细胞至关重要 认识到这种疾病。我们的假设是，接受免疫治疗的胶质母细胞瘤患者 在个体中安装针对特定突变和剪接变体的抗肿瘤免疫反应 肿瘤。同样，我们最近的其他发现有力地表明，PD-1抗体(MAb)的添加具有阻断作用 在临床前研究中，TO DCVAX增强了肿瘤内CD8+T细胞的反应和临床益处。 此外，PD-1单抗阻断的时机在免疫学上是相关的；我们最近进行的未发表的临床试验 结果强调了PD-1单抗阻断的新辅助治疗(手术前)是如何诱导增强的 抗肿瘤免疫反应和临床效益。我们假设PD-1单抗的加入可以阻断 应在血液中放大DC疫苗诱导的新抗原特异性T细胞反应 还有肿瘤。为了测试这些重要的问题，在目标1中，我们将开发一条新的生物信息学管道来 预测发生在GBM中的特定类型的基因改变所产生的新抗原。在《目标2》中，威尔 建立具有免疫功能的小鼠胶质瘤模型，以测试新抗原的重要性。最后，在目标3中，我们将 GBM患者TIL和外周血中新抗原特异性T细胞的鉴定 用免疫疗法。这些研究跨越了脑肿瘤免疫治疗的转译研究的连续过程。 并可能为开发新的、基于理性免疫的策略提供信息丰富的新见解 脑瘤患者。

SUMMARY/ABSTRACT The lack of effective glioblastoma treatments poses a significant health problem and highlights the need for novel and innovative approaches. Immunotherapy is an appealing strategy because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells in the brain. New information suggests that patients mounting immune responses after immunotherapy preferentially recognize novel neoantigens created by tumor-specific mutations. Our data, and that from other immunotherapeutic strategies for patients with cancer, suggest that the vast majority of tumor-specific T cells induced by such personalized, patient-specific immunotherapies do NOT recognize well-characterized, known antigens. Such information is consistent with recent data from other immune-responsive cancers, such as melanoma, in which the percentage of tumor-specific T cells recognizing known antigens was less than 1%. In order to design the most effective immunotherapeutic strategies for glioblastoma, we believe that it is critical to understand which antigens tumor-specific T cells recognize in this disease. Our hypothesis is that glioblastoma patients treated with immunotherapy will mount anti-tumor immune responses against specific mutations and splice variants in their individual tumors. Similarly, our other recent findings strongly suggest that the addition of PD-1 antibody (mAb) blockade to DCVax enhances both the intra-tumoral CD8+ T cell response and clinical benefit in pre-clinical studies. Furthermore, the timing of PD-1 mAb blockade is immunologically relevant; our unpublished, recent clinical trial results highlight how the neoadjuvant (prior to surgery) treatment with PD-1 mAb blockade induces enhanced anti-tumor immune responses and clinical benefit. We hypothesize that the addition of PD-1 mAb blockade should amplify the neoantigen-specific T cell response induced by DC vaccination, both in the blood and the tumor. To test these important questions, In Aim 1, we will develop a new bioinformatics pipeline to predict neoantigens that arise specifically from the types of genetic alterations that occur in GBM. In Aim 2, will create immunocompetent murine glioma models to test the importance of neoantigens. Finally, in Aim 3, we will identify neoantigen-specific T cells from both the TIL population and peripheral blood of GBM patients treated with immunotherapy. These studies span the continuum of translational research in brain tumor immunotherapy and will likely provide informative new insights for the development of new, rational immune-based strategies for brain tumor patients.