Designer antigen receptors to re-direct T cells to the NY-ESO-1 tumor antigen

描述（由申请人提供）：本次NCI职业发展奖的候选人是Marcela Valderrama Maus， MD, PhD，她目前是纪念斯隆-凯特琳癌症中心（MSKCC）的血液学和医学肿瘤学研究员。Maus博士长期对肿瘤免疫学、基因和细胞疗法感兴趣。她的论文工作是关于人类CD4和CD8 T细胞的激活和共刺激需求，这是通过使用含有多种共刺激分子的人工抗原提呈细胞来探索的，其中最著名的是4-1BB。她还完成了一项简短的博士后研究，在那里她发现了在血友病b的临床试验中接受基因转移的患者的衣壳特异性记忆T细胞。在MSKCC，她加入了Michel Sadelain实验室，这是T细胞治疗和基因转移领域的全球领导者。候选人的近期目标是完成本提案的目标，其中心是设计和测试针对细胞质肿瘤抗原NY-ESO-1的新形式抗原受体。这些目标的完成将为候选人提供新的技术技能，智力进步，以及在此基础上建立她在免疫治疗和基因转移方面的实验室基础职业。候选人的长期目标是成为一名学术医学肿瘤学家，开发和使用基于细胞的疗法来治疗黑色素瘤等实体肿瘤。

DESCRIPTION (provided by applicant): The candidate for this NCI Career Development Award is Marcela Valderrama Maus, MD, PhD, who is currently a hematology and medical oncology fellow at Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Maus has a long-standing interest in tumor immunology and gene and cell therapies. Her thesis work was on the activation and costimulation requirements of human CD4 and CD8 T cells, which was explored with the use of artificial antigen presenting cells bearing multiple costimulatory molecules, most notably 4-1BB. Dr. Maus also completed a brief post-doctoral fellowship where she identified capsid-specific memory T cells in patients who had undergone gene transfer in a clinical trial of hemophilia B. At MSKCC, Dr. Maus has joined the laboratory of Michel Sadelain, a worldwide leader in the field of T cell therapy and gene transfer. An immediate term goal of the candidate is to complete the Aims in this proposal, which center around designing and testing new forms of antigen receptors directed to a cytoplasmic tumor antigen, NY-ESO-1. The completion of these aims will provide the candidate with the candidate with new technical skills, intellectual advancement, and a substrate on which to build her laboratory-based career in immunotherapy and gene transfer. The long-term goal of the candidate is to become an academic medical oncologist who develops and uses cell-based therapies to treat solid tumors such as melanoma. Over the past decade, the adoptive transfer of T cells has emerged as an effective therapy in some patients with hematological malignancies or melanoma, but the process of generating these cells has been labor-intensive and not widely applicable due to the low frequency of tumor-specific T cells. The candidate's mentor is at the forefront in the development of adoptive T cell therapy with cells transduced with chimeric antigen receptors that re-direct them toward native surface antigens. Here, the candidate proposes to expand the concept of chimeric antigen receptors by targeting a cytoplasmic antigen with an antibody-based receptor (Aim 1) and a modified T cell receptor (Aim 2). These two new forms of designer antigen receptors will be characterized and compared in re-directed T cells with respect to affinity, co-receptor binding, immune synapse formation, and ex vivo and in vivo effector functions (Aim 3). MSKCC is an ideal site for this project because of the intellectual and technical resources available, and because of the institutional history and commitment to this line of research. The tumor antigen targeted here was initially described at MSKCC; the physician-scientist community and melanoma service are ideally suited to support and aid the candidate as she transitions to independent investigation, and there is evidence of their unconditional support for the candidate. The candidate has access to prior mentors, all highly respected physician scientists, and her current mentor has a track record of successfully training and launching other physician scientists; in addition, she has enlisted three leaders in the field of immunotherapy to serve on an advisory committee as she navigates the transition to independent investigation. This career development award will greatly enhance Dr. Marcela Valderrama Maus's research proposal and professional development.