Adoptive T cell Therapy for Patients with NY-ESO-1 Expressing Sarcomas

描述(由申请人提供)：应聘者的职业目标是成为一家转化免疫学实验室的首席研究员(PI)，该实验室将开发治疗晚期肉瘤患者的免疫治疗方法。在短期内，候选人的目标是通过执行本提案中概述的研究来获得翻译研究人员的经验。这项工作的核心是，候选人将作为I期试验的PI，在结合干扰素γ的新的调节方案的背景下，检查自体NY-ESO-1特异性CD8T细胞在表达NY-ESO-1的晚期肉瘤患者中的使用情况。这是一项候选人撰写、设计和开发了大部分临床前基础的试验。通过担任这项试验的PI，候选人将获得进行过继免疫治疗试验的经验，并获得从该试验收集和分析数据的经验。此外，该试验将作为平台，启动多项基于实验室的翻译研究，调查试验中患者的免疫逃逸机制，以及改进后续试验的策略。这项试验将在弗雷德·哈钦森癌症研究中心进行，该中心是临床和翻译研究的理想环境，也是T细胞免疫疗法试验领域的领先者。斯坦利·里德尔博士是国际知名的癌症免疫学和采用T细胞疗法试验专家，也是一位经验丰富和成功的导师，他将担任候选人的主要导师。这位候选人还组建了一个由资深教员组成的指导团队，每个教员都在各自的特定研究领域拥有国际知名的专业知识：Robin Jones(在 他们分别是：马丁(Mac)Cheever(擅长实体肿瘤免疫治疗试验)和Cassian Yee(擅长抗原特异性T细胞治疗试验)。该方案的具体目的如下：目的1：在一项I期试验中，评价干扰素γ、环磷酰胺(CY)和小剂量IL-2联合应用于晚期MRCL和SS患者的毒性、持久性和抗肿瘤活性。目的：探讨过继T细胞治疗SS和MRCL患者中抗原缺失突变体的出现情况，以及扩大其适用性和增强抗原性的策略。目的：探讨分离NY-ESO-1特异性CD4T细胞用于过继治疗增强或维持CD8T细胞功能的策略。

DESCRIPTION (provided by applicant): The candidate's career goal is to become a principal investigator (PI) of a translational immunology laboratory that will develop immunotherapeutic approaches towards the treatment of patients with advanced sarcoma. In the immediate term, the candidate aims to gain experience as a translational researcher by performing the studies outlined in this proposal. Central to this effort, the candidate will serve as the PI of the phaseI trial examining the use of autologous NY-ESO-1 specific CD8+ T cells for patient with advanced NY-ESO-1 expressing sarcomas in the context of a novel conditioning regimen which incorporates IFNγ. This is a trial that the candidate has written, designed and developed much of the preclinical foundation for. By serving as PI for this trial, the candidate will gain experiece in conducting an adoptive immunotherapy trial, and gain experience collecting and analyzing data from this trial. Additionally, the trial will serve as the platform to initiate multiple labortory-based translational studies investigating mechanisms of immune escape for patients on the trial and strategies to improve successor trials. The trial will be conducted at the Fred Hutchinson Cancer Research Center, an ideal environment for clinical and translational research and a leader in the field of T-cell immunotherapy trials. Dr. Stanley Riddell, an internationally renowned expert in cancer immunology and adoptive T cell therapy trials who is also an experienced and successful mentor, will serve as the primary to mentor the candidate. The candidate has also assembled a mentoring team comprised of senior faculty each with internationally renowned expertise in their particular field of research: Robin Jones (expertise in sarcoma clinical care and clinical trials), Martin (Mac) Cheever (expertise in solid tumor immunotherapy trials) and Cassian Yee (expertise in antigen specific T cell therapy trials). The specific aims of the proposal are as follows: Aim 1: To evaluate in a Phase I trial, the toxicity, persistence and antitumor activity of autologous NY- ESO-1 specific CD8+ cells administered with a novel conditioning regimen incorporating IFNγ, Cyclophosphamide (CY) and low dose IL-2 for patients with advanced MRCL and SS. Aim 2: To evaluate the emergence of antigen loss variants and strategies to broaden the applicability and enhance antigenicity of SS and MRCL patients receiving adoptive T cell therapy. Aim 3: To evaluate strategies to isolate NY-ESO-1 specific CD4+ T-cells for adoptive therapy to enhance or maintain CD8+ T cell function.