Programming T Cells for Successful Adoptive Cell Therapy

对 T 细胞进行编程以实现成功的过继细胞治疗

基本信息

批准号：
8133731
负责人：
Claudia Marcela Diaz-Montero
金额：
$ 13.06万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-18 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133731
关键词：
Achyrocline Affect Antigens Award CD8B1 gene Cancer Immunology Science Cell Therapy Cells Characteristics Clinical Conduct Clinical Trials Effector Cell Environment Extramural Activities Foundations Funding Generations Goals Homing Human Human Characteristics Immune Immune response Immunologic Memory Immunotherapy In Vitro Institutes Interleukin-12 Investments K-Series Research Career Programs Laboratories Lymphoid Memory Mentors Mentorship Mus Organ Phenotype Physiological Population Process Recruitment Activity Regimen Research Role SELL gene Scientist Stimulus T memory cell T-Lymphocyte Testing Time Training Universities Xenograft Model Xenograft procedure base cancer immunotherapy cancer therapy cytokine defined contribution design experience in vivo interest lymph nodes melanoma novel programs receptor retroviral transduction success tumor tumor progression

项目摘要

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.

描述（由申请人提供）：该职业发展奖的长期目标是将候选人 C. Marcela Diaz-Montero 博士培养成为一名独立的转化科学家。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，其中包括研究和校外资金指导，以及有关临床试验的设计、实施和进行的教育部分。该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。她发现，在 IL-12 存在的情况下，CD8+ T 细胞的抗原依赖性激活会导致具有早期激活表型 (TEA) 的 T 细胞亚群的积累。在体内，TEA 显示出增强的存活率和增强的抗肿瘤活性。基于这些观察结果，推测 TEA 具有增强的到达次级淋巴器官的能力；它们的不成熟表型使它们能够在最佳刺激条件下完成激活过程，从而产生具有更强抗肿瘤能力和卓越免疫记忆的效应细胞。为了检验这一假设，提出了以下具体目标： 1) 定义归巢到淋巴结对转移的 TEA 的存活和成熟的贡献； 2) 确定 TEA 存活率的提高是否是由于其可塑性赋予细胞因子库竞争优势； 3）确定增强型TEA对T细胞记忆生成的影响； 4) 测试IL-12存在下的激活对人TCR转导的T细胞的表型和功能特征的影响。更好地了解 CD8+ T 细胞的编程和分化将使我们能够识别最适合癌症 ACT 治疗的子集，并设计出有效的策略来增强该子集的生成和存活。此外，这些研究为候选人的研究项目奠定了基础，通过密切指导，该项目将发展成为最先进的、外部资助的癌症免疫治疗项目。导师 Joseph Rosenblatt 博士和 Eli Gilboa 博士是癌症免疫学和过继细胞治疗领域的专家，拥有丰富的指导经验。此外，迈阿密大学还对该候选人进行了大量投资，这反映了她实现拟议目标的潜力。 Diaz-Montero 博士被招募为多德森跨学科免疫治疗研究所计划的一部分，旨在开发高影响力和广泛有用的免疫疗法。她的招聘方案包括启动资金和实验室空间。总之，该奖项将为候选人提供保护时间来进行她提出的研究，并充分利用迈阿密大学现有的优秀机构环境，最终目标是成为癌症免疫治疗领域成功的转化科学家。