Cell-Selective, Repetitive, Irreversible Electroporation to Augment Mesothelioma CAR T-Cell Therapy
Abstract
Our proposal addresses the following Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: Mesothelioma, Immunotherapy, Liver Cancer, Pancreatic Cancer, and Stomach Cancer. The proposed research is relevant to active duty Service members and Veterans who are at high risk for development of mesothelioma and other cancers mentioned above. We have demonstrated that patients with malignant pleural mesothelioma (MPM) who have a higher ratio of anti-cancer immune cells (T cells) to pro-cancer immune cells, which suppress immune functions, have prolonged survival. To precisely target cancer cells, we have utilized a genetic engineering technology to synthesize artificial receptors in T cells called chimeric antigen receptors (CARs). CAR-transduced T cells traffic to, target, and kill cancer cells without help from other immune cells. The efficacy of CAR T-cell therapy has been established in the treatment of therapy-resistant blood cancers where patients with expected lifespans of a few months are able to prolong life for 3 to 6 years with no evidence of cancer relapse. These dramatic effects have resulted in Food and Drug Administration (FDA) approval for CAR T-cell therapy for leukemia and lymphoma within the past few months. With the support from the Department of Defense Technology Development Fund, we developed CARs that target mesothelin (MSLN), which is a protein overexpressed on cancer-cell surface. Mesothelin is associated with aggressiveness in MPM and other solid tumors such as colorectal, stomach, liver, lung, and pancreatic cancers, all of which are at a higher prevalence in Veterans and military personnel. We have now translated these MSLN-targeted CARs to clinical trials and have successfully treated 14 patients (NCT02414269 and NCT02792114) to date. Concurrent with our clinical trials, studies performed in animal models in our lab suggest that CAR T cells face hurdles to infiltrating the tumor that negatively impacts their function and poses a challenge to successful immunotherapy. In our proposal, we will exploit a novel technology known as irreversible electroporation (IRE) to modulate the tumor environment, thereby enhancing immunotherapeutic efficacy. While IRE is designed to kill cancer cells by disrupting their cell membrane, we aim to develop strategies to selectively kill larger cells (cancer) while simultaneously providing benefit to smaller (immune) cells without affecting their viability. The objective of this proposal is to develop new techniques for locoregional delivery of IRE non-invasively through the chest wall to augment infiltration of CAR T cells into tumors and further enhance their anti-cancer function by cell-selective, repetitive application (designed to be toxic to cancer cells while sparing T cells) of IRE to achieve durable therapy response. Our central hypothesis is that IRE-induced release of proteins, known as chemokines, will attract infiltration of CAR T cells into tumors and cell-selective IRE can enhance their survival and antitumor efficacy. While IRE performed with invasive needle electrodes is already in use at our center to destroy tumors in patients in situ, we rationalize that IRE at reduced doses can be designed to make its effects cell-selective and induce a release of factors from cancer cells that can facilitate immune cell infiltration (observations from preliminary experiments in the Co-Principal Investigator’s [PI’s] lab); this can promote the anti-cancer efficacy of CAR T cells (preliminary observations from the PI’s lab). We will investigate our hypothesis using clinically relevant mouse models of MPM utilizing MSLN-targeted CARs that are already being used in clinical trials. The use of non-invasive, cell-selective IRE to modify the immune status of a tumor to promote CAR T-cell function is previously undescribed, innovative, and a new paradigm in addressing a fundamental challenge to solid tumor immunotherapy. Impact: Mesothelin-targ
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810227
Entities
People
- Prasad S Adusumilli
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army