Novel Use of Malignant Pleural Effusion Resident T cells for Systemic Adoptive Cell Transfer in Veterans with Lung Cancer

恶性胸腔积液常驻 T 细胞在患有肺癌的退伍军人中进行系统过继细胞移植的新用途

• 批准号: 10012047
• 负责人: Rajeev Dhupar
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012047
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Aftercare; Autologous; Automobile Driving; Award; Benign; Bioenergetics; CD8B1 gene; Cancer Etiology; Cancer Patient; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Clinical; Clinical Data; Clinical Trials; Dichloroacetate; Disease; Drainage procedure; Effectiveness; Environment; Excision; Foundations; Genus Hippocampus; Glycolysis; Glycolysis Pathway; Immune; Immune System Diseases; Immunotherapy; In Situ; Incubated; Indwelling Catheter; Interferon Type II; Interferons; Interleukin-15; Interleukin-2; Lead; Leukocytes; Liquid substance; Malignant Neoplasms; Malignant Pleural Effusion; Malignant neoplasm of lung; Mediator of activation protein; Medical Waste; Metabolic; Metabolic dysfunction; Metastatic Melanoma; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Nutrient; Operative Surgical Procedures; Oxygen; Oxygen Consumption; Pathway interactions; Patients; Peripheral; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Phenotype; Pleural effusion disorder; Preparation; Prevalence; Production; Protocols documentation; Route; Site; Solid; Solid Neoplasm; Source; T cell receptor repertoire sequencing; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; TFRC gene; Time; Tumor Burden; Tumor Expansion; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Veterans; cancer cell; clinical application; cytokine; cytotoxicity; effusion; exhaust; exhaustion; glucose uptake; immune checkpoint blockade; insight; lymphoid neoplasm; melanoma; metabolic fitness; neoantigens; neoplastic cell; novel; palliate; palliation; personalized immunotherapy; physical property; pre-clinical; programmed cell death protein 1; respiratory; response; tumor; tumor infiltrating lymphocyte therapy; tumor-immune system interactions

Systemic immune checkpoint blockade and adoptive cell transfer (ACT) therapies have been used successfully in high mutational burden tumors such as non-small cell lung cancer (NSCLC) and melanoma, resulting in objective response and longer survival. For ACT, surgery is often required to obtain solid tumor infiltrating lymphocytes (TIL), which must then be isolated and expanded due to their small quantities. Alternatively, malignant pleural effusions (MPEs) that occur in advanced NSCLC have abundant tumor and immune cells. These are palliated with drainage, and the fluid is discarded as medical waste. However, our preliminary observations indicate that MPEs may contain a subset of immune cells which can be activated toward anti- tumor activity. These abundant immune cells could be a source for adoptive cell transfer therapy with the advantages of (1) being readily available without surgery and (2) possibly requiring less expansion. I hypothesize that there is a subset of T cells in NSCLC MPEs which can be used for ACT therapy. The objective of this proposal is to optimize and expand tumor specific T cells from NSCLC MPEs for ACT therapy. This proposal will undertake studies that establish critical pre-clinical data en-route to a clinical trial with adoptive T cell transfer in Veterans with lung cancer. Thirty pleural effusions and 10 solid lung cancer tumors will be collected as medical waste from patients undergoing clinically indicated drainage or surgery. The first Aim will compare anti-tumor reactivity of MPE resident T cells (MPET) to traditional TIL and determine T cell receptor repertoire and tumor mutational burden for neoepitope prediction. The second Aim will characterize the bioenergetic state of MPET that are trapped in the metabolically hostile environment of a pleural effusion. We will define the mechanisms of T cell metabolic dysfunction in a pleural effusion, and also study alterations on anti-tumor activity after metabolically reprograming T cells with a commercially available modulator of the glycolysis pathway. The third and final Aim will determine if MPET can be successfully expanded to sufficient quantities for ACT therapy without reaching terminal exhaustion. We will also optimize the metabolic state of MPET to enhance activity after expansion. Together, the proposed studies will provide insight about an unexplored tumor environment with potential to provide large quantities of readily accessible tumor specific immune cells. This project may lead to the use of immune cells from MPE as a source for adoptive cell transfer therapy in Veterans with NSCLC.

系统性免疫检查点阻断和过继细胞转移（ACT）疗法已经成功使用