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Immunotherapeutic targeting of the Glioblastoma Mutanome

胶质母细胞瘤突变组的免疫治疗靶向

基本信息

批准号：
8996139
负责人：
DAVID ANDREW LARGAESPADA
金额：
$ 20.01万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-16 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8996139
关键词：
Animals Antigens Autologous Brain Neoplasms Cancer Vaccines Cells Clinical Clinical Trials Code Data Data Set Dendritic Cells Development Disease Epitopes Exhibits Glioblastoma Glioma Health Human Immune Immune response Immunity Immunocompetent Immunologic Monitoring Immunotherapeutic agent Immunotherapy In Vitro Individual Life Malignant Glioma Malignant Neoplasms Methods Modeling Mus Mutation Patient Care Patients Phase Physiologic pulse Pre-Clinical Model Research Sampling Site Somatic Mutation Specimen T cell response T-Lymphocyte Testing Therapeutic Tumor Antigens Tumor Immunity Vaccinated Vaccination design exome sequencing glioma cell line immunogenicity in vivo innovation melanoma mouse model neoplastic cell novel outcome forecast personalized immunotherapy preclinical study response synthetic peptide trafficking tumor vaccination strategy vaccine trial

项目摘要

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.

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重大的健康问题，并强调了对新颖和创新方法的需求。免疫疗法是一种有吸引力的策略，因为免疫细胞具有运输和破坏浸润性肿瘤细胞的潜在能力。在过去的十年中，我们的团队和其他人一直在测试主动疫苗接种策略，例如用肿瘤裂解物或合成肽脉冲的树突状细胞在胶质母细胞瘤患者中诱导抗肿瘤免疫。然而，我们的数据以及其他针对癌症患者的免疫策略表明，这种个性化的患者特异性免疫疗法诱导的绝大多数肿瘤特异性T细胞不能识别特征明确的已知抗原。为了设计针对胶质母细胞瘤的最有效的免疫策略，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至关重要。最近的信息表明，免疫治疗后产生免疫应答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，用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体肿瘤中的特定突变产生抗肿瘤免疫应答。此外，我们假设具有延长的存活期的患者将对这些新抗原产生更多样化的抗肿瘤免疫应答。为了测试这一点，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疫苗接种治疗的胶质母细胞瘤患者中的非同义突变。然后，我们将筛选和鉴定用于神经胶质瘤特异性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的DC疫苗接种后优先扩增。我们还将在我们的原位小鼠胶质瘤模型中设计一组平行的临床前研究。我们将在两个鼠神经胶质瘤细胞系的非同义突变的特点，并随后确定由鼠神经胶质瘤特异性T细胞识别的显性新抗原。为了扩大这一点，我们将用鉴定的胶质瘤特异性新抗原接种小鼠，并评估哪些抗原赋予携带颅内胶质瘤的小鼠有效的抗肿瘤免疫力。该项目可能具有变革性，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疗法。本文提出的研究可能对胶质母细胞瘤患者的个性化癌症疫苗的开发具有重要意义。