Immunotherapeutic targeting of the Glioblastoma Mutanome

 描述(由申请人提供)：缺乏有效的胶质母细胞瘤治疗仍然是一个严重的健康问题，并突出了对新的和创新的方法的需要。免疫治疗是一种吸引人的策略，因为免疫细胞具有潜在的运输和摧毁浸润性肿瘤细胞的能力。在过去的十年里，我们的团队和其他人一直在测试积极的疫苗接种策略，例如用肿瘤裂解物或合成肽冲击的树突状细胞来诱导胶质母细胞瘤患者的抗肿瘤免疫。然而，我们的数据以及癌症患者的其他免疫治疗策略的数据表明，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征的已知抗原。为了设计最有效的胶质母细胞瘤免疫治疗策略，我们认为了解肿瘤特异性T细胞在这种疾病中识别哪些抗原是至关重要的。最近的信息表明，免疫治疗后增强免疫反应的患者可以识别由肿瘤特异性突变产生的新抗原。我们的假设是，接受自体肿瘤裂解物脉冲DC疫苗治疗的胶质母细胞瘤患者将针对其个别肿瘤中的特定突变产生抗肿瘤免疫反应。此外，我们假设生存期延长的患者将对这些新抗原产生更多样化的抗肿瘤免疫反应。为了验证这一点，我们建议对患者肿瘤标本进行外显子组测序，以识别接受DC疫苗治疗的胶质母细胞瘤患者的非同义突变。然后，我们将筛选和鉴定胶质瘤特异性T细胞识别的候选表位，并最终评估哪些新表位特异性T细胞在自体肿瘤裂解物脉冲DC疫苗接种后优先扩增。我们还将在我们的原位小鼠脑胶质瘤模型中设计一组平行的临床前研究。我们将鉴定两个小鼠胶质瘤细胞系中的非同义突变，并随后确定小鼠胶质瘤特异性T细胞所识别的主要新抗原。为了扩大这一范围，我们将用识别出的胶质瘤特异性新抗原接种小鼠，并评估哪些抗原能赋予携带脑胶质瘤的小鼠有效的抗肿瘤免疫。这个项目可能具有潜在的变革性，因为更好地了解恶性胶质瘤中的相关新抗原可能会极大地改变这种致命疾病的免疫治疗。本文提出的研究可能对胶质母细胞瘤患者个性化癌症疫苗的开发具有重要意义。

 DESCRIPTION (provided by applicant): The lack of effective glioblastoma treatments remains 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. For the past decade, our group and others have been testing active vaccination strategies, such as dendritic cells pulsed with tumor lysates or synthetic peptides to induce antitumor immunity in glioblastoma patients. However, our data, and that of other immunotherapeutic strategies for patients with cancer, suggest that the vast majority of tumor-specific T cells induced by this personalized, patient-specific immunotherapy do NOT recognize well-characterized, known antigens. 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. Recent information suggests that patients mounting immune responses after immunotherapy can recognize novel neoantigens created by tumor-specific mutations. Our hypothesis is that glioblastoma patients treated with autologous tumor lysate-pulsed DC vaccination will mount anti-tumor immune responses against specific mutations in their individual tumor. Furthermore, we hypothesize that patients with extended survival will have mounted more diverse anti-tumor immune responses to such neoantigens. To test this, we propose to perform exome sequencing on patient tumor specimens to identify nonsynonymous mutations in glioblastoma patients treated with DC vaccination. We will then screen and identify candidate epitopes for glioma-specific T cell recognition, and finally evaluate which neoepitope- specific T cells are preferentially expanded following autologous tumor lysate-pulsed DC vaccination. We will also design a set of parallel pre-clinical studies in our orthotopic murine glioma model. We will characterize nonsynonymous mutations in two murine glioma cell lines, and subsequently identify dominant neoantigens recognized by murine glioma-specific T cells. To expand this, we will then vaccinate mice with identified glioma-specific neoantigens and evaluate which antigens confer effective anti-tumor immunity to mice bearing intracranial gliomas. This project could potentially be transformative, as a better understanding of the relevant neoantigens in malignant glioma could dramatically alter immunotherapy for this deadly disease. The studies proposed herein could have important implications for the development of personalized cancer vaccines in glioblastoma patients.