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

系统性免疫检查点阻断和过继性细胞转移（ACT）疗法已成功使用 在高突变负荷肿瘤如非小细胞肺癌（NSCLC）和黑色素瘤中， 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肿瘤浸润 淋巴细胞（TIL），由于其数量少，必须分离和扩增。可选择地， 晚期NSCLC中发生的恶性胸腔积液（MPE）具有丰富的肿瘤细胞和免疫细胞。 这些都是减轻与排水，和液体被丢弃的医疗废物。然而，我们的初步 观察表明，MPE可能含有一个免疫细胞亚群，其可以被激活以抗- 肿瘤活性这些丰富的免疫细胞可能是过继细胞转移治疗的来源， 优点是（1）无需手术即可获得和（2）可能需要较少的扩张。我 假设NSCLC MPE中存在可用于ACT治疗的T细胞亚群。的 该提案的目的是优化和扩增来自NSCLC MPE的肿瘤特异性T细胞用于ACT治疗。 该提案将开展研究，建立临床试验过程中的关键临床前数据， 肺癌患者的过继性T细胞转移胸腔积液30例，肺癌实体瘤10例 将作为医疗废物收集，这些废物来自正在接受临床引流或手术的患者。第一 目的比较MPE驻留T细胞（MPE-resident T cells，MPET）与传统TIL的抗肿瘤反应性， 用于新表位预测的受体库和肿瘤突变负荷。 第二个目标将表征被困在代谢敌对的MPET的生物能量状态， 胸腔积液的环境。我们将明确胸膜炎患者T细胞代谢功能障碍的机制， 渗出，并研究在代谢重编程T细胞后抗肿瘤活性的变化， 糖酵解途径的市售调节剂。 第三个也是最后一个目标将决定MPET是否可以成功地扩大到ACT的足够数量 治疗而不达到终端衰竭。我们还将优化MPET的代谢状态， 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， 提供大量容易获得的肿瘤特异性免疫细胞。该项目可能导致使用 MPE免疫细胞作为非小细胞肺癌退伍军人过继性细胞转移治疗的来源。

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.