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Tumor Genetics and Response to Checkpoint Blockade in Melanoma and Ovarian Cancer

黑色素瘤和卵巢癌的肿瘤遗传学和检查点阻断的反应

基本信息

批准号：
9013345
负责人：
Alexandra Snyder Charen
金额：
$ 18万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9013345
关键词：
Advanced Malignant Neoplasm Advisory Committees Antigens CD8B1 gene CTLA4 gene Cancer cell line Cell Line Cell model Characteristics Clinical Correlative Study Cytotoxic Chemotherapy Cytotoxic T-Lymphocyte-Associated Protein 4 DNA Damage DNA Sequence Alteration Data Educational Curriculum Engraftment Exposure to Faculty Genetic Goals Gynecologic Oncology Immune system Immunologist Immunotherapy In Vitro Induced Mutation Lung Malignant Neoplasms Malignant neoplasm of ovary Memorial Sloan-Kettering Cancer Center Mentorship Metastatic Melanoma Modality Mus Mutagenesis Mutation Organism Outcome Ovarian Patients Peptides Pharmaceutical Preparations Poly(ADP-ribose) Polymerases Prior Chemotherapy Recurrence Research Research Personnel Sampling Scientist Somatic Mutation Structure T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Work base chemotherapeutic agent cohort cytotoxic defined contribution exome genetic analysis genomic predictors improved in vivo Model inhibitor/antagonist knowledge base melanoma member mouse model pathogen patient subsets peripheral blood phase II trial preclinical study predicting response predictive marker public health relevance research study response tumor

项目摘要

DESCRIPTION (provided by applicant): Immunotherapy, including T-cell checkpoint inhibition, has rapidly changed the outcome of advanced cancers in a subset of patients. To extend benefit of these promising therapies to more patients, we must delineate predictive biomarkers and develop approaches to enhance the efficacy of checkpoint blockade. Our long-term goal is to define the contribution of tumor genetics to clinical benefit from checkpoint blockade immunotherapies and to use this information to develop better therapeutic modalities. Our group has shown that an elevated mutational burden correlates with benefit from therapy in melanoma patients treated with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) therapies. For the proposed project, we have collected melanoma tumors (N=42) from pembrolizumab-treated patients and will perform the correlative genetics analyses for a Phase II trial of nivolumab ± ipilimumab in advanced ovarian cancer (planned accrual, N=96). Using these samples, in Aim 1 we will examine our working hypothesis that an elevated mutational burden increases the likelihood of response to checkpoint blockade in melanoma and ovarian cancers. We will then integrate T cell receptor (TCR) sequencing data available from the melanoma tumors and peripheral blood to investigate the hypothesis that TCR oligoclonal dominance will add to mutational burden as a predictor of response. In Aim 2, we will identify and clone neoantigen-specific T cells from melanoma patients treated with pembrolizumab, and then use these clones to investigate our hypothesis that neoantigen-specific T cells can be activated by homologous peptides. Finally, in Aim 3, we will characterize whether therapy-induced DNA damage can sensitize melanoma and ovarian cancer cell lines to checkpoint blockade therapy using in vitro and in vivo models of melanoma and ovarian cancer. These experiments will determine whether therapy-induced mutagenesis can sensitize tumors to checkpoint blockade therapy. The preclinical and correlative studies outlined in this proposal have the potential to (a) elucidate mechanisms of response to immunotherapy in two fatal cancers, and (b) provide data to begin to answer the clinically important question of whether non-immunogenic tumors can be sensitized to checkpoint blockade therapy by inducing mutations. The studies will be led by Dr. Alexandra Snyder, a junior faculty member at Memorial Sloan Kettering Cancer Center under the mentorship of Dr. Timothy Chan, a leading tumor geneticist; Dr. Jedd Wolchok, a renowned tumor immunologist; and Dr. Carol Aghajanian, a world leader in Gynecologic Oncology. To achieve her long-term goal of become an independent investigator, Dr. Snyder has assembled an advisory committee of leading scientists, and has developed a structured curriculum aimed at deepening her knowledge base so she can advance the field.

描述(由申请人提供)：免疫治疗，包括T细胞检查点抑制，已经迅速改变了部分患者的晚期癌症结果。为了将这些有希望的治疗方法的益处扩大到更多的患者，我们必须描述预测性生物标志物，并开发方法来提高检查点封锁的疗效。我们的长期目标是确定肿瘤遗传学对检查点阻断免疫疗法的临床益处的贡献，并利用这些信息开发更好的治疗方式。我们小组已经证明，在接受抗CTLA4(细胞毒性T淋巴细胞相关蛋白4)治疗的黑色素瘤患者中，突变负担的增加与治疗的益处相关。在拟议的项目中，我们收集了接受培布罗利珠单抗治疗的患者的黑色素瘤(N=42)，并将为nivolumab±ipilimumab治疗晚期卵巢癌(计划应计，N=96)的II期试验进行相关的遗传学分析。使用这些样本，在目标1中，我们将检验我们的工作假设，即突变负担增加增加了对黑色素瘤和卵巢癌检查点阻断的反应的可能性。然后，我们将整合来自黑色素瘤肿瘤和外周血的T细胞受体(TCR)测序数据，以研究TCR寡克隆优势将增加突变负担作为应答预测因子的假设。在目标2中，我们将从接受培溴利珠单抗治疗的黑色素瘤患者中鉴定和克隆新抗原特异性T细胞，然后使用这些克隆来验证我们的假设，即新抗原特异性T细胞可以被同源多肽激活。最后，在目标3中，我们将使用黑色素瘤和卵巢癌的体外和体内模型来表征治疗诱导的DNA损伤是否可以使黑色素瘤和卵巢癌细胞株对检查点阻断治疗敏感。这些实验将确定治疗诱导的突变是否可以使肿瘤对检查点阻断治疗敏感。这项建议中概述的临床前研究和相关研究有可能(A)阐明两种致命癌症对免疫治疗的反应机制，以及(B)为开始回答非免疫原性肿瘤是否可以通过诱导突变而对检查点阻断治疗敏感这一临床重要问题提供数据。这些研究将由亚历山德拉·斯奈德博士领导，她是纪念斯隆·凯特琳癌症中心的初级教员，在著名肿瘤遗传学家蒂莫西·陈博士、著名肿瘤免疫学家杰德·沃尔乔克博士和妇科肿瘤学世界领先者卡罗尔·阿加贾尼安博士的指导下进行。为了实现成为一名独立研究人员的长期目标，斯奈德博士组建了一个由顶尖科学家组成的顾问委员会，并制定了一套结构化的课程，旨在加深她的知识基础，使她能够在该领域取得进步。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade.

用CTLA-4封锁处理的黑色素瘤中的体细胞突变和新EPITOPE同源性。

DOI：
10.1158/2326-6066.cir-16-0019
发表时间：
2017-01
期刊：
Cancer immunology research
影响因子：
10.1
作者：
Nathanson T;Ahuja A;Rubinsteyn A;Aksoy BA;Hellmann MD;Miao D;Van Allen E;Merghoub T;Wolchok JD;Snyder A;Hammerbacher J
通讯作者：
Hammerbacher J