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: 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
• 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

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博士确定为独立的转化科学家。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，实施和行为的教育组成部分。候选人的研究兴趣集中在增强T淋巴细胞对过养细胞疗法的活性。她已经做出了新的观察结果，即在存在IL-12的情况下，CD8+ T细胞的抗原依赖性激活导致与早期激活表型（TEA）的T细胞亚群的积累。在体内，茶秀增强了生存率和抗肿瘤活性的增加。基于这些观察结果，假设茶具有增强的到达次级淋巴器官的能力。并且其不成熟的表型使他们能够在最佳刺激条件下通过激活过程进行进展，从而导致抗肿瘤能力和优质免疫记忆具有更强的效应细胞。为了检验该假设，正在提出以下特定目的：1）定义对淋巴结对转移茶的生存和成熟的贡献； 2）确定茶的生存是否增强是由于其可塑性赋予了细胞因子水槽的竞争优势； 3）确定增强茶对T细胞记忆产生的影响； 4）测试IL-12存在激活对人TCR转导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确定最适合癌症ACT治疗的子集，并设计有效的策略，以增强该子集的产生和生存。此外，这些研究代表了候选人的研究计划的基础，通过密切指导将发展为癌症免疫疗法的最先进的，外部资助的计划。导师约瑟夫·罗森布拉特（Joseph Rosenblatt）和埃利·吉尔博亚（Eli Gilboa）博士是癌症免疫学领域和具有丰富指导经验的收养细胞疗法的专家。此外，迈阿密大学对候选人进行了巨大的投资，这反映了她实现自己的目标的潜力。 Diaz-Montero博士被招募为Dodson跨学科免疫疗法研究所的一部分，以开发高影响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。总而言之，该奖项将为候选人的保护时间提供她的拟议研究，并充分利用迈阿密大学获得的杰出机构环境，最终的目标是成为成功的转化科学家。