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

• 批准号: 7934010
• 负责人: Claudia Marcela Diaz-Montero
• 金额: $ 12.78万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/7934010
• 关键词: Achyrocline; Affect; Antigens; Arts; 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; Tea; 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

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）：这个职业发展奖的长期目标是建立候选人，博士C。Marcela Diaz-Rocco，独立翻译科学家。为了实现这一目标，候选人，同时与她的导师，设计了一个全面的培训计划，其中包括研究和校外资助辅导，以及对设计，实施和临床试验的进行教育的组成部分。候选人的研究兴趣集中在增强过继细胞治疗的T淋巴细胞的活性。她已经做出了新的观察，即在IL-12存在下CD 8 + T细胞的抗原依赖性活化导致具有早期活化表型（TEA）的T细胞亚群的积累。在体内，TEA显示出增加的存活率和增加的抗肿瘤活性。基于这些观察，假设TEA具有增强的到达次级淋巴器官的能力;并且它们的未成熟表型允许它们在最佳刺激条件下通过活化过程进展，从而产生具有更强抗肿瘤能力和上级免疫记忆的效应细胞。为了验证这一假设，提出了以下具体目标：1）确定归巢至淋巴结对转移的TEA的存活和成熟的贡献; 2）确定TEA的存活增强是否是由于它们的可塑性赋予细胞因子汇的竞争优势; 3）确定增强的TEA对T细胞记忆产生的影响; 4）测试在IL-12存在下活化对人TCR转导的T细胞的表型和功能特征的影响。更好地理解CD 8 + T细胞的编程和分化将使我们能够确定最适合ACT治疗癌症的子集，并设计有效的策略来提高该子集的生成和存活。此外，这些研究代表了候选人的研究计划的基础，通过密切的指导将发展成为最先进的，在癌症免疫治疗的校外资助计划。导师Joseph Rosenblatt博士和Eli吉尔博亚博士是癌症免疫学和过继细胞治疗领域的专家，具有丰富的导师经验。此外，迈阿密大学对这位候选人进行了重大投资，这反映了她实现其提出的目标的潜力。Diaz-Barrio博士被招募为Dodson跨学科免疫治疗研究所计划的一部分，以开发高影响力和广泛有用的免疫治疗。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，以进行她提出的研究，并充分利用迈阿密大学的优秀机构环境，最终目标是成为癌症免疫治疗领域的成功转化科学家。