Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies

Abstract

Chimeric antigen receptor (CAR) T cells are patient T cells that are transduced with genetically engineered synthetic receptors to target a cancer cell surface antigen. 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. Herein, we review the evolution of adoptive T-cell therapy; highlight advances in CAR T-cell therapy for thoracic malignancies; and summarize the targets being investigated in clinical trials for patients with lung cancer, malignant pleural mesothelioma, and esophageal cancer. We further discuss the barriers to successfully translating CAR T-cell therapy for solid tumors and present strategies that have been investigated to overcome these hurdles.

Incorporation of Immune Checkpoint Blockade into Chimeric Antigen Receptor T Cells (CAR-Ts): Combination or Built-In CAR-T

“…The reason for this difference between tumors is being actively explored, and is likely multifactorial. One primary reason for this disparity is the tumor-intrinsic mechanisms and the associated tumor microenvironment that play an important role in the inhibition of the antitumor immune response [ 14 ]. It is well established that solid malignancies create an environment that can impede T cell activity.…”

“…This includes the presence of regulatory T cells (Tregs), tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), and cancer-associated fibroblasts, that promote higher levels of inhibitory ligands and cytokines. These phenomena appear to extend in part to liquid tumors as evidenced by elevated numbers of Tregs in CLL and DLBCL [ 14 , 15 ]. Further, tumor indoleamine 2,3-dioxygenase (IDO) is known to inhibit CD19-CAR-T cells in a xenograft lymphoma model expressing IDO [ 15 ].…”

Making cold malignant pleural effusions hot: driving novel immunotherapies

“…Candidate target antigens currently being investigated in clinical trials for lung cancer and MM include overexpressed tumor-associated antigens (TAAs) [carcinoembryonic antigen (CEA), ganglioside (GD2), glypican-3 (GPC3), human epidermal growth factor receptor 2 (HER2), mesothelin (MSLN), epidermal growth factor (EGFR), prostate stem cell antigen (PSCA), and receptor tyrosine-kinase-like orphan receptor (ROR1)]; abnormal glycosylation proteins [transmembrane glycoprotein mucin 1 (MUC1)]; immunomodulatory antigens [NKG2D ligands including MICA/MICB and ULBP1-3, PD-L1, CD80/CD86]; and stromal elements associated with the tumor microenvironment [fibroblast activation protein (FAP) and VEGF Receptor 2]. 233,242 EGFR and HER2 are receptor tyrosine kinases that are amplified or mutated in a variety of cancers, including over 15% of NSCLC patients in western nations and 45% of NSCLC patients in Asian countries. 243,244 Second generation EGFR-CAR T cells (CD3 + CD8 + T cells) demonstrated high proliferative capacity as well as specific and potent cytotoxicity against NSCLC cells in vitro and in vivo.…”

Chimeric Antigen Receptor T-Cell Therapy for Colorectal Cancer

“…Clinical trials of CAR T-cell therapy in thoracic malignancies are scarce. The main targets for CARs of esophageal cancer were epithelial cell adhesion molecule (EpCAM) and HER2 [97]. We found one experimental study that targeted EphA2 for esophageal squamous cell carcinoma (ESCC) CAR T-cell construction.…”