CAR-Based Cell Therapy in Head and Neck Cancer: A Comprehensive Review on Clinical Applicability

Abstract

Background/Objectives: Chimeric antigen receptor T-cell (CAR-T) therapy is a novel form of adoptive cellular immunotherapy that involves modifying autologous T cells to recognize and target tumor-associated antigens (TAAs) on malignant cells, independent of major histocompatibility complex (MHC) restriction. Although CAR-T therapy has shown remarkable success in treating hematologic malignancies, its efficacy in solid tumors remains limited, largely due to the lack of tumor-specific antigens and the complexity of the tumor microenvironment. This review aims to explore the rationale for continuing the development of adoptive cellular therapies in head and neck cancer (HNC), offering insights into the diagnostic and therapeutic challenges associated with this heterogeneous group of malignancies. Methods: We conducted a comprehensive literature review using the PubMed database to identify relevant studies on the application of CAR-T cell therapy in the management of HNC. Results: HNC presented numerous barriers to CAR-T cell infiltration, primarily due to the unique characteristics of its tumor microenvironment (TME). The TME in HNC is notably immunosuppressive, with a lymphocytic infiltrate predominantly composed of regulatory T cells (Tregs) and natural killer (NK) cells. These immune cells typically exhibit low expression of the CD16 receptor, which plays a crucial role in mediating antibody-dependent cellular cytotoxicity (ADCC), thereby limiting the effectiveness of CAR-T cell therapy. Conclusions: This comprehensive review suggests a potential clinical applicability of CAR-T therapy in HNC management.

Keywords: CAR-T; head and neck cancer; immune checkpoint; immunotherapy; tumor microenvironment.

Figure 1

CAR-T cell therapy is based on the creation of specific T cells capable of recognizing a specific antigen towards which the receptor is directed. It starts from the hypothetical structure of the receptor, which, converted into nucleic acid, is transfected into T cells taken from the patient. The latter are re-infused into the patient.

Figure 2

Over time, different types of CAR-T cells have been generated; the first-generation CAR-T cells have a very simple structure and, apart from the variable IGG domain, they possess the intracellular domain of CD3; the second-generation CAR-T cells possess an additional domain, i.e., a co-stimulatory molecule, and their use is accompanied by greater efficacy and a greater probability of eliciting a cancer-specific immune response; the third- and fourth-generation CAR-T cells have more co-stimulatory domains (third generation) and a sequence capable of coding for an immunostimulatory cytokine (fourth generation).