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

描述(由申请人提供)：NCI职业发展奖的候选人是Marcela Valderrama Maus，医学博士，目前是纪念斯隆-凯特琳癌症中心(MSKCC)的血液学和肿瘤学研究员。Maus博士长期以来一直对肿瘤免疫学、基因和细胞疗法感兴趣。她的论文工作是关于人类CD4和CD8T细胞的激活和共刺激需求，这是通过使用携带多个共刺激分子的人造抗原提呈细胞来探索的，最明显的是4-1BB。Maus博士还完成了一项短暂的博士后研究，在血友病B的临床试验中，她在接受基因转移的患者中发现了衣壳特异的记忆T细胞。在MSKCC，Maus博士加入了T细胞治疗和基因转移领域的全球领导者Michel Sadelain的实验室。候选人的近期目标是完成这项提案中的目标，该提案围绕设计和测试针对细胞质肿瘤抗原NY-ESO-1的新形式的抗原受体。这些目标的完成将为候选人提供新的技术技能、智力进步和在实验室建立免疫治疗和基因转移职业生涯的基础。候选人的长期目标是成为一名学术肿瘤学家，开发和使用基于细胞的疗法来治疗黑色素瘤等实体肿瘤。 在过去的十年里，T细胞的过继转移已经成为一些血液系统恶性肿瘤或黑色素瘤患者的一种有效治疗方法，但由于肿瘤特异性T细胞的频率较低，产生这些细胞的过程一直是劳动密集型的，并且不能广泛应用。这位候选人的导师在开发过继T细胞疗法方面走在了前列，通过转导嵌合抗原受体的细胞将它们重新定向到天然表面抗原。在这里，候选人建议扩大嵌合抗原受体的概念，通过靶向具有基于抗体的受体(AIM 1)和修饰的T细胞受体(AIM 2)的细胞质抗原。这两种新形式的设计型抗原受体将在重定向的T细胞中从亲和力、共受体结合、免疫突触形成以及体外和体内效应功能方面进行表征和比较(目标3)。 MSKCC是这个项目的理想地点，因为有可用的智力和技术资源，以及机构历史和对这一研究领域的承诺。这里针对的肿瘤抗原最初是在MSKCC描述的；医生-科学家社区和黑色素瘤服务非常适合在候选人过渡到独立研究时支持和帮助她，而且有证据表明他们对候选人的无条件支持。候选人可以接触到以前的导师，他们都是备受尊敬的内科科学家，她现在的导师有成功培训和启动其他内科科学家的记录；此外，她还招募了免疫疗法领域的三位领导人在她过渡到独立调查的过程中担任顾问委员会的成员。这一职业发展奖将极大地促进Marcela Valderrama Maus博士的研究提案和专业发展。

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.