Metabolic Reprogramming of Tumor Infiltrating Lymphocytes for Adoptive Immunotherapy

肿瘤浸润淋巴细胞的代谢重编程用于过继免疫治疗

• 批准号: 9975113
• 负责人: Udai S Kammula
• 金额: $ 35.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-09 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975113
• 关键词: ARG2 gene; Adoptive Cell Transfers; Adoptive Immunotherapy; Adoptive Transfer; Antigens; Apoptosis; Autologous; Autologous Tumor-Infiltrating Lymphocyte; Automobile Driving; Bioenergetics; Biological Assay; Biomedical Engineering; CD8B1 gene; Cancer Patient; Cell Death; Cell physiology; Cells; Cellular Metabolic Process; Chronic; Clinical Trials; Cutaneous Melanoma; Data; Development; Enzymes; Future; Genetic; Genetic Engineering; Genetic Transcription; Goals; Grant; Human; Immunodeficient Mouse; Immunotherapy; Infusion procedures; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Memory; Metabolic; Metabolism; Methods; Mitochondria; Molecular; Mutation; Neoplasm Metastasis; Pathway interactions; Patients; Pharmacology; Proteomics; Regulation; Reporter; Reporting; Resistance; Respiration; Role; Safety; Signal Pathway; Signal Transduction; T cell differentiation; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Tumor Antigens; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Up-Regulation; Uveal Melanoma; Xenograft Model; cancer immunotherapy; cell type; chromatin immunoprecipitation; clinically relevant; detection of nutrient; effector T cell; engineered T cells; exhaust; experience; fitness; improved; in vivo; metabolomics; novel; novel strategies; overexpression; pre-clinical; prevent; promoter; stem; systemic toxicity; transcription factor; transcriptome; tumor; tumor infiltrating lymphocyte therapy; tumor microenvironment; tumor xenograft; ARG2 gene; Adoptive Cell Transfers; Adoptive Immunotherapy; Adoptive Transfer; Antigens; Apoptosis; Autologous; Autologous Tumor-Infiltrating Lymphocyte; Automobile Driving; Bioenergetics; Biological Assay; Biomedical Engineering; CD8B1 gene; Cancer Patient; Cell Death; Cell physiology; Cells; Cellular Metabolic Process; Chronic; Clinical Trials; Cutaneous Melanoma; Data; Development; Enzymes; Future; Genetic; Genetic Engineering; Genetic Transcription; Goals; Grant; Human; Immunodeficient Mouse; Immunotherapy; Infusion procedures; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Memory; Metabolic; Metabolism; Methods; Mitochondria; Molecular; Mutation; Neoplasm Metastasis; Pathway interactions; Patients; Pharmacology; Proteomics; Regulation; Reporter; Reporting; Resistance; Respiration; Role; Safety; Signal Pathway; Signal Transduction; T cell differentiation; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Tumor Antigens; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Up-Regulation; Uveal Melanoma; Xenograft Model; cancer immunotherapy; cell type; chromatin immunoprecipitation; clinically relevant; detection of nutrient; effector T cell; engineered T cells; exhaust; experience; fitness; improved; in vivo; metabolomics; novel; novel strategies; overexpression; pre-clinical; prevent; promoter; stem; systemic toxicity; transcription factor; transcriptome; tumor; tumor infiltrating lymphocyte therapy; tumor microenvironment; tumor xenograft

Abstract Adoptive cell transfer using autologous tumor infiltrating lymphocytes (TIL) represents a personalized cancer immunotherapy strategy targeting shared and unique tumor antigens expressed by a patient's cancer. Although originally developed for cutaneous melanoma therapy, we recently reported TIL therapy can be effective against metastatic uveal melanoma (UM), a cancer with low mutational burden and resistance to conventional immunotherapies. A significant limitation in improving upon these results is that the vast majority of antigen experienced TIL will undergo cell death shortly following infusion. Only a small subset persist as long-lived memory cells. This may stem from the limited metabolic reserve of highly differentiated effector T cells (TEFF). Chronic antigen exposure can result in deficiencies in nutrient sensing and flux through critical bioenergetic and biosynthetic pathways that support T cell activation, proliferation, and effector functions. Ex vivo metabolic reprograming could rescue “exhausted” TEFF and promote development of long-lived memory cells following adoptive transfer. Our long-term goal is to develop clinically relevant approaches that promote the metabolic fitness of human TIL following adoptive transfer. 4-1BB (CD137) co-stimulatory signaling can transiently improve the metabolic capacity of human tumor specific CD8+ TEFF. Our preliminary findings demonstrate that this metabolic improvement is dependent upon a novel mechanism employing the activity of the mitochondrial enzyme, arginase 2 (ARG2). Thus, the specific objective of this grant is to further characterize the role of ARG2 in reprogramming the fate and function of highly differentiated TEFF. Our central hypothesis is that ARG2 is the critical mediator of the improved metabolism found in TEFF following 4-1BB co-stimulation. Since 4-1BBL expression is often deficiently expressed by tumors, we, consequently, postulate that bioengineering TEFF to conditionally express ARG2 upon TCR stimulation will reprogram their cellular metabolism in the tumor microenvironment, improving in vivo persistence and function. We anticipate that these studies will enhance the metabolic fitness of TIL for future adoptive transfer clinical trials. To test our hypothesis, we propose the following Specific Aims: Aim 1. Identify key transcriptional regulators linking 4-1BB co-stimulation with ARG2 activity in human TEFF cells. Aim 2. Characterize the downstream metabolic and cellular effects of ARG2 expression in TEFF cells. Aim 3. Determine the safety and efficacy of adoptive transfer of human TIL bioengineered to express ARG2 in patient derived tumor xenograft models. Collectively, the completion of these studies will demonstrate the essential role of enhanced ARG2 expression in promoting and sustaining T cell metabolism. Bioengineered expression of ARG2 could markedly improve adoptive immunotherapy with TIL.

抽象的 使用自体肿瘤浸润淋巴细胞（TIL）的收养细胞转移代表个性化癌症 针对患者癌症表达的共享和独特肿瘤抗原的免疫疗法策略。虽然 我们最初是为皮肤黑色素瘤疗法开发的，我们最近报道 转移性卵子黑色素瘤（UM），一种癌症，突变烧伤低，对常规的抗性 免疫疗法。改善这些结果的一个重要局限性是绝大多数抗原 经验丰富的TIL将在输注后不久将发生细胞死亡。只有一个小子集持续了长寿 记忆单元。这可能源于高度分化效应T细胞（TEFF）的代谢储备有限。 慢性抗原暴露会导致营养感应和通过临界生物能量的不足和通量 支持T细胞激活，增殖和效应子功能的生物合成途径。离体代谢 重新编程可以挽救“疲惫”的TEFF并促进长寿记忆单元的发展 收养转移。我们的长期目标是开发促进代谢的临床相关方法 自适应转移后，人类的适应性。 4-1BB（CD137）共刺激信号传导可以暂时改进 人类肿瘤特异性CD8+ TEFF的代谢能力。我们的初步发现证明了这一点 代谢改善取决于采用线粒体活性的新型机制 酶，精氨酸酶2（arg2）。这是这笔赠款的具体目标是进一步描述Arg2的作用 在重新编程高度分化的TEFF的命运和功能时。我们的核心假设是Arg2是 4-1BB共刺激后，TEFF中发现的改善新陈代谢的关键介体。自4-1BBL以来 表达通常由肿瘤清楚地表达 在TCR刺激时有条件表达ARG2将重新编程其在肿瘤中的细胞代谢 微环境，改善体内持久性和功能。我们预计这些研究将增强 TIL用于未来自适应转移临床试验的代谢适应性。为了检验我们的假设，我们提出以下内容 具体目的：目标1。确定关键转录调节器将4-1BB共同刺激与ARG2活动联系起来 人teff细胞。 AIM 2。表征TEFF中Arg2表达的下游代谢和细胞效应 细胞。目的3。确定人类TIL生物工程以表达Arg2的自适应转移的安全性和效率 在患者衍生的肿瘤特征模型中。总的来说，这些研究的完成将证明 增强ARG2表达在促进和维持T细胞代谢中的重要作用。生物工程 ARG2的表达可以显着改善TIL的适应性免疫疗法。