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: 10316150
• 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/10316150
• 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.

全身免疫检查点阻断和过继性细胞移植（ACT）疗法已成功使用 在非小细胞肺癌（NSCLC）和黑色素瘤等高突变负荷肿瘤中，导致 客观反应和更长的生存期。对于 ACT，通常需要手术以获得实体瘤浸润 淋巴细胞 (TIL)，由于数量较少，必须对其进行分离和扩增。或者， 晚期 NSCLC 中发生的恶性胸腔积液 (MPE) 含有丰富的肿瘤和免疫细胞。 这些可以通过引流来缓解，并且液体被作为医疗废物丢弃。然而，我们的初步 观察结果表明，MPE 可能含有免疫细胞的子集，这些细胞可以被激活以对抗 肿瘤活性。这些丰富的免疫细胞可能成为过继细胞转移疗法的来源 优点是（1）无需手术即可轻松获得，（2）可能需要较少的扩张。我 假设 NSCLC MPE 中有一个 T 细胞亚群可用于 ACT 治疗。这 该提案的目标是优化和扩展 NSCLC MPE 中的肿瘤特异性 T 细胞，用于 ACT 治疗。 该提案将进行研究，在临床试验过程中建立关键的临床前数据 患有肺癌的退伍军人的过继性 T 细胞移植。 30例胸腔积液和10例实体肺癌 将作为医疗废物从接受临床指示引流或手术的患者身上收集。第一个 Aim 将比较 MPE 驻留 T 细胞 (MPET) 与传统 TIL 的抗肿瘤反应性并确定 T 细胞 新表位预测的受体库和肿瘤突变负荷。 第二个目标将描述 MPET 的生物能状态，这些状态被困在代谢不利的环境中。 胸腔积液的环境。我们将定义胸膜腔中 T 细胞代谢功能障碍的机制 渗出液，并研究用代谢重编程 T 细胞后抗肿瘤活性的变化 市售的糖酵解途径调节剂。 第三个也是最后一个目标将决定 MPET 是否可以成功扩展到足够数量以供 ACT 使用 治疗未达到最终疲惫。我们还将优化MPET的代谢状态，以增强 扩张后的活动。 总之，拟议的研究将提供有关未探索的肿瘤环境的见解，有潜力 提供大量易于获得的肿瘤特异性免疫细胞。该项目可能会导致使用 来自 MPE 的免疫细胞作为 NSCLC 退伍军人过继细胞转移治疗的来源。