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

基本信息

批准号：
9815770
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
项目类别：
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/9815770
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

项目摘要

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) 的过继细胞转移代表了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治疗策略。最初开发用于皮肤黑色素瘤治疗，我们最近报道 TIL 疗法可以有效对抗转移性葡萄膜黑色素瘤 (UM)，一种突变负荷低且对传统药物具有耐药性的癌症免疫疗法改善这些结果的一个显着限制是绝大多数抗原。经历过的 TIL 在输注后不久就会发生细胞死亡，只有一小部分细胞会长期存活。这可能源于高度分化的效应 T 细胞 (TEFF) 的代谢储备有限。慢性抗原暴露可能导致营养感应和通过关键生物能和通量的缺陷。支持 T 细胞激活、增殖和效应器功能的生物合成途径。重编程可以拯救“耗尽”的 TEFF 并促进长寿命记忆细胞的发育我们的长期目标是开发促进代谢的临床相关方法。过继转移后人类 TIL 的适应性可以暂时改善。我们的初步研究结果表明，人类肿瘤特异性 CD8+ TEFF 的代谢能力。代谢改善依赖于利用线粒体活性的新机制因此，这项资助的具体目标是进一步表征 ARG2 的作用。在重编程高度分化的 TEFF 的命运和功能中，我们的中心假设是 ARG2 是自 4-1BBL 以来，TEFF 中发现 4-1BB 共刺激后新陈代谢改善的关键介质。肿瘤的表达通常有缺陷，因此，我们假设生物工程 TEFF 在 TCR 刺激下条件性表达 ARG2 将重新编程肿瘤中的细胞代谢我们预计这些研究将增强微环境，改善体内持久性和功能。 TIL 对于未来过继转移临床试验的代谢适应性为了检验我们的假设，我们提出以下建议。具体目标：目标 1. 确定将 4-1BB 共刺激与 ARG2 活性联系起来的关键转录调节因子目标 2. 表征 TEFF 中 ARG2 表达的下游代谢和细胞效应。目标 3. 确定通过生物工程改造表达 ARG2 的人 TIL 过继转移的安全性和有效性总的来说，这些研究的完成将证明：增强的 ARG2 表达在促进和维持 T 细胞代谢中的重要作用。 ARG2 的表达可以显着改善 TIL 的过继免疫治疗。