TCR TRANSDUCED CDB T CELLS FOR ADOPTIVE IMMUNOTHERAPY

用于过继免疫治疗的 TCR 转导 CDB T 细胞

• 批准号: 8744928
• 负责人: MICHAEL I. NISHIMURA
• 金额: $ 28.57万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-04 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744928
• 关键词: Address; Adoptive Immunotherapy; Affect; Affinity; Antibodies; Antigen Presentation; Antigens; Biology; CD34 gene; CD8B1 gene; Cell Survival; Cell physiology; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Complex; Cyclophosphamide; Data; Dendritic Cells; Development; Environment; Gene-Modified; Generations; Genes; HLA-A2 Antigen; Human; Immunotherapy; In Vitro; Integration Host Factors; Interleukin-12; Interleukin-15; Interleukin-2; Leukocytes; Lymphocyte; Lymphoid; Lymphopenia; Memory; Modeling; Monophenol Monooxygenase; Mus; Patients; Peripheral; Phase I Clinical Trials; Phenotype; Positioning Attribute; Protocols documentation; Reagent; Regimen; Series; Signal Transduction; Source; Specificity; T cell response; T-Lymphocyte; Transgenic Mice; Transgenic Organisms; Translational Research; Treatment Efficacy; Tumor Immunity; Tumor Suppression; Vaccination; cell growth; conditioning; design; expectation; fludarabine; in vivo; insight; long term memory; meetings; melanoma; novel; pre-clinical; preconditioning; programs; receptor; research clinical testing; response; tool; trafficking; tumor; tumor microenvironment

The concept of antigen specific TCR transduced lymphocytes for adoptive immunotherapy is gaining increasing support. For this to become a reality, however, the biology and in vivo response of these cells to the host environment, including tolerance, antigen presentation, and tumor microenvironment will have to be carefully delineated. Our translational research group recently has developed a series of novel observations/reagents to address this issue. First, we have observed that cyclophosphamide (CTX) preconditioning induces post-lymphopenia expansion of DC in the PBL. Second, we have delineated that IL- 12 conditioning during in vitro priming is able to promote the acquisition of an early effector (TEA) like phenotype. Both are associated with enhanced anti-tumor responses in vivo. Third, our program collaborator (Dr. Shikar Mehrotra) has successfully created a TCR transgenic mouse (termed h3T) which expresses functional melanoma antigen (tyrosinase) specific human TCR in peripheral CD8+ T cells thus providing a source of naive endogenous T cells expressing tyrosinase specific TCR and TCR transduced T cells of the same specificity. We hypothesize that combining the antigen specific response of TCR transduced CD8+ T cells with an environment which promotes DC function will result in the generation of more effective anti-tumor immunity. Therefore, we propose the following: Specific Aim 1 will define the impact of homeostatic proliferation and mechanisms of IL-12 conditioning on TCR transduced T cell survival and function in a tumor bearing host. We will then assess the mechanisms by which IL-12 conditioning impacts on TCR transduced and h3T transgenic T cell survival looking specifically at CTLA-4, PD-1 signaling. Specific Aim 2 will define the TCR transduced CD8+ T cell response to antigen presentation in an environment which promotes DC function evaluating both the post-lymphopenia expansion of DC environment, and also with a limited lymphopenia post CD8+ antibody depletion. PBL from the phase I clinical trial will be used to confirm our preclinical data for both aims. Finally, Specific Aim 3 will determine the optimal conditions required to induce a robust memory TCR transduced CD8+ T cell response in a tumor bearing environment evaluating the mechanisms affecting in vivo TCR transduced CD8+ T cells responses We will then define the therapeutic efficacy of TCR transduced T-cells adoptively transferred into a tumor bearing mouse. Using these novel tools to probe the mechanisms involved in the in vivo response of TCR transduced T cells to the host environment should provide an ability to design more effective adoptive immunotherapy protocols.

用于过继免疫治疗的抗原特异性 TCR 转导淋巴细胞的概念正在获得越来越多的支持。然而，要使这成为现实，必须仔细描述这些细胞对宿主环境的生物学和体内反应，包括耐受性、抗原呈递和肿瘤微环境。我们的转化研究小组最近开发了一系列新颖的观察/试剂来解决这个问题。首先，我们观察到环磷酰胺 (CTX) 预处理会诱导 PBL 中 DC 的淋巴细胞减少后扩增。其次，我们已经描述了体外启动过程中的 IL-12 调节能够促进早期效应器 (TEA) 样表型的获得。两者都与体内增强的抗肿瘤反应有关。第三，我们的项目合作者（Shikar Mehrotra 博士）成功创建了 TCR 转基因小鼠（称为 h3T），其在外周 CD8+ T 细胞中表达功能性黑色素瘤抗原（酪氨酸酶）特异性人类 TCR，从而提供了表达酪氨酸酶特异性 TCR 的幼稚内源性 T 细胞来源和具有相同特异性的 TCR 转导 T 细胞。我们假设将 TCR 转导的 CD8+ T 细胞的抗原特异性反应与促进 DC 功能的环境相结合将产生更有效的抗肿瘤免疫。因此，我们提出以下建议：具体目标 1 将定义稳态增殖的影响以及 IL-12 调节对 TCR 转导的 T 细胞在荷瘤宿主中存活和功能的影响。然后，我们将评估 IL-12 调节对 TCR 转导和 h3T 转基因 T 细胞存活的影响机制，特别关注 CTLA-4、PD-1 信号传导。具体目标 2 将定义 TCR 转导的 CD8+ T 细胞对环境中抗原呈递的反应，该环境促进 DC 功能，评估 DC 环境的淋巴细胞减少后扩张，以及 CD8+ 抗体耗尽后有限的淋巴细胞减少。 I 期临床试验的 PBL 将用于确认我们针对这两个目标的临床前数据。最后，具体目标 3 将确定在荷瘤环境中诱导强大的记忆 TCR 转导 CD8+ T 细胞反应所需的最佳条件，评估影响体内 TCR 转导 CD8+ T 细胞反应的机制，然后我们将定义过继转移到荷瘤小鼠体内的 TCR 转导 T 细胞的治疗功效。使用这些新工具来探究 TCR 转导的 T 细胞对宿主环境的体内反应机制，应该能够设计出更有效的过继免疫治疗方案。