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.
Lung cancer is the #1 cause of cancer related deaths for Veterans, with a prevalence almost twice as high as the non-Veteran population. Adoptive cell transfer (ACT) therapy shows promise for lung cancer but requires surgical removal of solid tumor and expansion of immune cells which can result in suboptimal function. Malignant pleural effusions (MPE) in advanced lung cancer are drained and discarded for palliation, however they have an abundance of immune cells that are a readily accessible and could be used for ACT therapy. This application presents preliminary observations that MPE derived immune cells may harbor anti-tumor activity and proposes studies to understand the potential for using them for ACT therapy in lung cancer patients. These studies may become the foundation for a novel clinical trial using personalized immunotherapy to treat lung cancer in Veterans.
