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.

Keywords: Adoptive cell therapy; Immunotherapy; T-cell therapy; Thoracic cancers.

Fig. 1

Scanning electron micrograph of CAR T cells pseudo colored (green) attacking a cultured MSLN-overexpressing malignant mesothelioma cell (blue). The T cells were genetically engineered to express a scFv that specifically targets MSLN. CAR, chimeric antigen receptor; MSLN, mesothelin

Fig. 2

Structure of CAR T cells. The extracellular domain is typically an antibody-derived scFv fused to a transmembrane and an intracellular signaling domain. While first generation CAR T cells contain only one intracellular signaling domain, such as the TCR-derived CD3ζ chain, second and third generation CAR T cells combine the signaling domain with one (second generation) or two or more (third generation) costimulatory domains such as CD28 or 4-1BB. The addition of costimulatory domains leads to increased proliferation and resistance to exhaustion. CAR, chimeric antigen receptor; scFv, single-chain variable fragment; TCR, T-cell receptor

Fig. 3

Antigen targets in CAR T-cell therapy clinical trials for thoracic malignancies. The targets shown are compiled from clinical studies listed on ClinicalTrials.gov (last assessed on 7/20/17) that specifically target thoracic malignancies with CAR T cells. There are no targets currently employed for thymic cancer; however, MSLN is a potential therapeutic target for thymic carcinoma. CAR, chimeric antigen receptor; CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor; EpCAM, epithelial cell adhesion molecule; FAP, fibroblast activating protein; GPC3, glypican-3; HER2, human epidermal growth factor receptor 2; MSLN, mesothelin; MUC1, mucin 1; PD-L1, programmed death-ligand 1; PSCA, prostate stem cell antigen; ROR1, receptor tyrosine kinase-like orphan receptor 1

Fig. 4

Multiplex immunofluorescence staining of patient tumors demonstrate key obstacles to CAR T-cell therapy for thoracic malignancies. (A) Tumor heterogeneity: Shown are MSLN-positive tumor cells in yellow. The arrowhead points to high antigen-expressing tumor cells and the arrows point to low antigen-expressing tumor cells. (B) Stroma as a barrier: Shown are tumor cells in yellow, TILs in green, and stromal components in red. (C) Immunosuppressive cells, such as tumor-associated macrophages, are shown in red interacting with TILs (green). (D) Immune checkpoint suppression via PD-1/PD-L1 axis. The arrowheads point to PD-L1-positive cells in magenta and the arrows point to PD-1-positive TILs. CAR, chimeric antigen receptor; MSLN, mesothelin; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TILs: tumor infiltrating lymphocytes