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: 8782916
• 负责人: Claudia Marcela Diaz-Montero
• 金额: $ 13.06万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8782916
• 关键词: Programming; Cells; Successful; Adoptive; Cell

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，候选人与她的导师一起设计了一个全面的培训计划，其中包括研究和校外资助指导，以及关于临床试验的设计、实施和实施的教育部分。候选人的研究兴趣集中在增强T淋巴细胞的活性，用于过继细胞治疗。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活化表型（TEA）的T细胞亚群的积累。在体内，TEA显示出增强的生存和抗肿瘤活性。基于这些观察结果，假设TEA具有增强的到达次级淋巴器官的能力；它们不成熟的表型允许它们在最佳刺激条件下通过激活过程，从而产生具有更强抗肿瘤能力和优越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)定义归巢到淋巴结对转移TEA存活和成熟的贡献；2)确定TEA存活率的提高是否由于其可塑性赋予了细胞因子汇的竞争优势；3)确定TEA增强对T细胞记忆生成的影响；4)检测IL-12存在下激活对人TCR转导T细胞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ACT治疗癌症的亚群，并设计有效的策略来增强该亚群的生成和存活。此外，这些研究为候选人的研究项目奠定了基础，通过密切的指导，该项目将发展成为癌症免疫治疗领域最先进的外部资助项目。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，具有丰富的指导经验。此外，迈阿密大学在这位候选人身上投入了大量资金，这反映了她实现自己提出的目标的潜力。Diaz-Montero博士被招募为Dodson跨学科免疫治疗研究所倡议的一部分，以开发高影响和广泛有用的免疫治疗方法。她的招聘计划包括启动资金和实验室空间。综上所述，该奖项将为候选人提供保护时间，以进行她拟议的研究，并充分利用迈阿密大学优秀的制度环境，最终目标是成为一名成功的癌症免疫治疗转化科学家。

项目成果

Phase 1 studies of the safety and immunogenicity of electroporated HER2/CEA DNA vaccine followed by adenoviral boost immunization in patients with solid tumors.

• DOI: 10.1186/1479-5876-11-62
• 发表时间: 2013-03-08
• 期刊: Journal of translational medicine
• 影响因子: 7.4
• 作者: Diaz CM;Chiappori A;Aurisicchio L;Bagchi A;Clark J;Dubey S;Fridman A;Fabregas JC;Marshall J;Scarselli E;La Monica N;Ciliberto G;Montero AJ
• 通讯作者: Montero AJ

Myeloid-Derived Suppressor Cell Subset Accumulation in Renal Cell Carcinoma Parenchyma Is Associated with Intratumoral Expression of IL1β, IL8, CXCL5, and Mip-1α.

• DOI: 10.1158/1078-0432.ccr-15-1823
• 发表时间: 2017-05-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Najjar YG;Rayman P;Jia X;Pavicic PG Jr;Rini BI;Tannenbaum C;Ko J;Haywood S;Cohen P;Hamilton T;Diaz-Montero CM;Finke J
• 通讯作者: Finke J