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

系统免疫检查点阻断和过继细胞转移(ACT)疗法已成功使用 在高突变负荷的肿瘤中，如非小细胞肺癌(NSCLC)和黑色素瘤，导致 客观反应和更长的生存时间。对于ACT，通常需要手术才能获得实体肿瘤的浸润性。 淋巴细胞(TIL)，由于数量较少，必须进行分离和扩增。或者， 晚期非小细胞肺癌患者的恶性胸腔积液(MPE)具有丰富的肿瘤细胞和免疫细胞。 这些都可以通过引流来缓解，这些液体作为医疗废物被丢弃。然而，我们的初步调查 观察表明，MPE可能包含一个免疫细胞亚群，可以被激活以对抗 肿瘤活动性。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，以及(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。这个 该方案的目的是优化和扩增非小细胞肺癌MPE细胞中的肿瘤特异性T细胞，用于ACT治疗。 这项提案将进行研究，以建立关键的临床前数据，并进行临床试验 退伍军人肺癌患者的过继T细胞转移。30例胸腔积液和10例肺癌实体瘤 将作为医疗废物从接受临床指征的引流或手术的患者中收集。第一 AIM将比较MPE驻留T细胞(MPET)和传统TIL的抗肿瘤活性，并确定T细胞 新表位预测的受体谱系和肿瘤突变负荷。 第二个目标将描述被困在新陈代谢敌意中的MPET的生物能量状态。 胸腔积液的环境。我们将明确胸腔积液中T细胞代谢功能障碍的机制 渗出，并研究抗肿瘤活性的变化后，代谢性重编程T细胞与 商业上可获得的糖酵解途径的调节剂。 第三个也是最终目标将决定MPET能否成功扩大到足以进行ACT的数量 治疗时不会出现终极疲惫。我们还将优化mpet的代谢状态，以增强 扩张后的活动。 总之，拟议的研究将提供对一个未被探索的肿瘤环境的洞察，具有潜在的 提供大量容易获得的肿瘤特异性免疫细胞。这个项目可能会导致使用 来自MPE的免疫细胞作为非小细胞肺癌退伍军人过继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.