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

总结/摘要 缺乏有效的胶质母细胞瘤治疗构成了一个重大的健康问题，并强调了对新的治疗方法的需要。 和创新的方法。免疫治疗是一种有吸引力的策略，因为免疫治疗具有潜在的免疫功能。 细胞运输并摧毁大脑中的浸润性肿瘤细胞。新的信息表明， 免疫治疗后的免疫应答优先识别由肿瘤特异性抗体产生的新抗原， 突变我们的数据以及其他癌症患者免疫策略的数据表明， 绝大多数肿瘤特异性T细胞由这种个性化的患者特异性免疫疗法诱导， 不识别特征明确的已知抗原。这些信息与最近的数据一致， 其他免疫应答癌症，如黑素瘤，其中肿瘤特异性T细胞的百分比 对已知抗原的识别率低于1%。为了设计出最有效的免疫系统 我们认为，关键是要了解哪些抗原肿瘤特异性T细胞 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 针对其个体中的特定突变和剪接变体产生抗肿瘤免疫应答， 肿瘤的同样，我们最近的其他研究结果强烈表明，PD-1抗体（mAb）阻断剂的加入， 在临床前研究中，DCVax增强了肿瘤内CD 8 + T细胞应答和临床益处。 此外，PD-1 mAb阻断的时机与免疫学相关;我们最近未发表的临床试验 结果强调了PD-1 mAb阻断的新辅助治疗（手术前）如何诱导增强的 抗肿瘤免疫应答和临床益处。我们假设PD-1 mAb阻断剂的加入 应该放大DC疫苗接种诱导的新抗原特异性T细胞应答， 还有肿瘤为了测试这些重要的问题，在目标1中，我们将开发一个新的生物信息学管道， 预测新抗原，特别是从GBM中发生的遗传变异类型产生的。在目标2中，将 建立免疫活性鼠神经胶质瘤模型以测试新抗原的重要性。在目标3中，我们将 从接受治疗的GBM患者的TIL群体和外周血中鉴定新抗原特异性T细胞 免疫疗法这些研究涵盖了脑肿瘤免疫治疗转化研究的连续性 并可能为开发新的，合理的基于免疫的策略提供信息丰富的新见解， 脑肿瘤患者

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 Furthermore, the timing of PD-1 mAb blockade is immunologically relevant; our unpublished, recent clinical trial results highlight how the neoadjuvant (prior to surgery) treatment with PD-1 mAb blockade induces enhanced anti-tumor immune responses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.