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

描述（由申请人提供）：候选人的职业目标是成为转化免疫学实验室的首席研究员（PI），该实验室将开发用于治疗晚期肉瘤患者的免疫治疗方法。在短期内，候选人旨在通过执行本提案中概述的研究来获得作为翻译研究人员的经验。作为这项工作的核心，该候选药物将作为i期试验的PI，该试验将在一种包含IFN¿的新型调理方案的背景下，研究自体NY-ESO-1特异性CD8+ T细胞对表达NY-ESO-1的晚期肉瘤患者的使用。这是一个候选人已经编写，设计和开发了很多临床前基础的试验。通过担任该试验的PI，候选人将获得开展过继性免疫治疗试验的经验，并获得收集和分析该试验数据的经验。此外，该试验将作为启动多个基于实验室的转化研究的平台，研究试验患者的免疫逃逸机制和改进后续试验的策略。该试验将在Fred Hutchinson癌症研究中心进行，该中心是临床和转化研究的理想环境，也是t细胞免疫治疗试验领域的领导者。Stanley Riddell博士是国际知名的癌症免疫学和过继性T细胞治疗试验专家，也是一位经验丰富且成功的导师，他将担任候选人的主要导师。候选人还组建了一个由在其特定研究领域具有国际知名专业知识的高级教师组成的指导团队

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 IFN¿. 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 IFN¿, 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.