Programming T Cells for Successful Adoptive Cell Therapy

描述(由申请者提供)：该职业发展奖的长期目标是确立候选人C.Marcela Diaz-蒙特罗博士作为一名独立翻译科学家的地位。为了实现这一目标，候选人与她的导师同时设计了一项全面的培训计划，其中包括研究和外部资金指导，以及关于临床试验的设计、实施和进行的教育部分。这位候选人的研究兴趣集中在增强T淋巴细胞的活性以进行过继细胞治疗。她做出了新的观察，即在IL-12存在的情况下，CD8 T细胞的抗原依赖性激活导致具有早期激活表型(TEA)的T细胞亚群的积累。在体内，茶表现出延长生存和增强抗肿瘤活性。基于这些观察，推测TEA具有更强的到达次级淋巴器官的能力；其不成熟的表型允许它们在最佳刺激条件下通过激活过程，从而产生更强的抗肿瘤能力和更好的免疫记忆。为了验证这一假设，提出了以下具体目标：1)确定归巢到淋巴结对转移的TEA的存活和成熟的贡献；2)确定TEA的增强存活率是否由于其可塑性而被赋予细胞因子汇的竞争优势；3)确定增强的TEA对T细胞记忆的产生的影响；4)测试在IL-12存在的情况下激活对人TCR转导的T细胞表型和功能特性的影响。更好地了解CD8T细胞的编程和分化将使我们能够确定最适合ACT治疗癌症的亚群，并设计有效的策略来增强这一亚群的生成和存活。此外，这些研究代表了候选人研究计划的基础，通过密切的指导，该计划将发展成为癌症免疫治疗中最先进的、由外部资助的计划。这两位导师约瑟夫·罗森布拉特博士和伊莱·吉尔博亚博士都是癌症免疫学和采用细胞疗法领域的专家，拥有丰富的导师经验。此外，迈阿密大学对这位候选人进行了大量投资，这反映了她实现拟议目标的潜力。迪亚兹-蒙特罗博士被招募为多德森跨学科免疫治疗研究所倡议的一部分，该倡议旨在开发高效果和广泛有用的基于免疫的治疗方法。她的招聘方案包括启动资金和实验室空间。总而言之，这一奖项将为候选人提供保护性时间，以进行她提议的研究，并充分利用迈阿密大学现有的杰出机构环境，最终目标是成为癌症免疫治疗领域的一名成功的转化科学家。

DESCRIPTION (provided by applicant): The long term goal of this career development award is to establish the candidate, Dr. C. Marcela Diaz-Montero, as an independent translational scientist. To achieve this goal, the candidate, concurrently with her mentors, has designed a comprehensive training plan that includes research and extramural funding mentoring, as well as an educational component on the design, implementation and conduct of clinical trials. The candidate's research interests focus on enhancing the activity of T lymphocytes for adoptive cell therapy. She has made the novel observation that antigen-dependent activation of CD8+ T cells in the presence of IL-12 results in the accumulation of a subpopulation of T cells with an early-activated phenotype (TEA). In vivo, TEA show augmented survival and increased anti-tumor activity. Based on these observations, it is hypothesized that TEA have an enhanced ability to reach secondary lymphoid organs; and that their immature phenotype allows them to progress through the activation process under optimal stimulatory conditions resulting in effector cells with stronger anti-tumor capabilities and superior immunologic memory. To test this hypothesis the following specific aims are being proposed: 1) Define the contribution of homing to the lymph node to the survival and maturation of transferred TEA; 2) Ascertain if enhanced survival of TEA is due to their plasticity conferring a competitive advantage for cytokine sinks; 3) Determine the impact of enhanced TEA on the generation of T cell memory; 4) Test the impact of activation in the presence of IL-12 on the phenotypic and functional characteristics of human TCR transduced T cells. A better understanding of the programming and differentiation of CD8+ T cells will allow us to identify the subset best fitted for ACT therapy for cancer and to design effective strategies that enhance the generation and survival of this subset. In addition, these studies represent the foundation for the candidate's research program that through close mentorship will develop into a state of the art, extramurally funded program in cancer immunotherapy. The mentors, Dr. Joseph Rosenblatt and Dr. Eli Gilboa, are experts in the field of cancer immunology and adoptive cell therapy with extensive mentorship experience. In addition, the University of Miami has made a significant investment in the candidate, which reflects on her potential to achieve her proposed goals. Dr. Diaz-Montero was recruited as part of the Dodson Interdisciplinary Immunotherapy Institute initiative to develop high-impact and broadly useful immune-based treatments. Her recruitment package included start up funds and laboratory space. In summary, this award will provide the candidate protective time to conduct her proposed studies and to fully exploit the outstanding institutional environment available at the University of Miami with the ultimate goal of becoming a successful translational scientist in cancer immunotherapy.