PL05.01 CAR T-cell Therapy for Thoracic Cancers

Abstract

Immunity against solid tumors is restricted by factors including limited tumor infiltration of T cells, antigen heterogeneity and suppressive tumor microenvironment. Adoptive cell therapy aims to overcome these limitations by administering cancer-antigen specific, genetically engineered T cells. Three main approaches are being tested in clinical trials. Adoptive transfer of tumor harvested and expanded lymphocytes combined with immune checkpoint inhibitory (ICI) agents is currently in clinical trials in thoracic cancers. TCR (T-cell receptor) T-cell therapy is the second strategy wherein patient-derived T lymphocytes are genetically modified to incorporate an antigen-targeting TCR, most of the targeted antigens are intracellular. Chimeric antigen receptor (CAR) T cells, the third approach to adoptive cell therapy uses patient’s own T cells that are transduced with genetically engineered synthetic receptors to target a cancer cell surface antigen. In addition, neoantigen-directed T-cell therapies are currently in clinical trials for thoracic cancers. CAR T cells are redirected to the tumor and are HLA-independent for their antigen activation and cancer cell lysis. The remarkable clinical response rates achieved by adoptive transfer of T cells that target CD19 in patients with leukemia and lymphoma have led to a growing number of clinical trials exploring CAR T-cell therapy for solid tumors. Our laboratory has developed, optimized and translated mesothelin, a cancer-cell surface antigen targeted CAR T-cell therapy. We have treated 41 thoracic cancer patients (mesothelioma, metastatic breast and lung cancers) to date with remarkable safety and evidence of anti-tumor efficacy. In this trial, patients were administered mesothelin-targeted CAR T cells intrapleural. We have previously published the immunological advantages of regional delivery of CAR T cells – early antigen activation, proliferation, augmented CD4-dependant immunity as well as systemic immunity. In a second clinical trial, patients with triple-negative breast cancer received systemically infused mesothelin-targeted CAR T cells. We further developed strategies to overcome the barriers to successfully translating CAR T-cell therapy for solid tumors. One such strategy already in clinic for patients with pleural mesothelioma is combination immunotherapy with CAR T cells and CPB agents. Checkpoint blockade therapy can elicit durable clinical responses by reactivating an exhausted immune response. However, response rates remain limited, likely secondary to a lack of a tumor-reactive immune infiltrate. CAR T cells may provide the necessary tumor-targeting immune infiltrate and a highly specific antitumor immune response. This can be further amplified by the addition of ICI agents, which serve to counteract the immune inhibitory environment undermining optimal CAR T-cell efficacy. Our phase I/II trial results will be discussed. Combination immunotherapies with cell therapy and ICI agents are in multiple clinical trials. Our recent approach incorporates T-cell intrinsic ICI strategy by a PD1 dominant negative receptor that is incorporated within the CAR, thereby the functional persistence of the T-cell is ensured. These trials are ongoing in patients with thoracic cancers. CAR T-cell therapy, Adoptive Cell Therapy, Mesothelin, Mesothelioma, Checkpoint Blockade agents