CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

Abstract

Chimeric antigen receptor (CAR) T cell therapy has garnered significant excitement due to its success for hematological malignancies in clinical studies leading to the US Food and Drug Administration (FDA) approval of three CD19-targeted CAR T cell products. In contrast, the clinical experience with CAR T cell therapy for solid tumors and brain tumors has been less encouraging, with only a few patients achieving complete responses. Clinical and preclinical studies have identified multiple "roadblocks," including (1) a limited array of targetable antigens and heterogeneous antigen expression, (2) limited T cell fitness and survival before reaching tumor sites, (3) an inability of T cells to efficiently traffic to tumor sites and penetrate physical barriers, and (4) an immunosuppressive tumor microenvironment. Herein, we review these challenges and discuss strategies that investigators have taken to improve the effector function of CAR T cells for the adoptive immunotherapy of solid tumors.

Graphical abstract

Figure 1

CAR T Cell Immunotherapy “Roadblocks” for Solid Tumors Top left: antigen dilemma. Heterogeneous antigen expression results in immune escape variants, and antigen expression in normal tissues can lead to on target/off cancer toxicity. Top right: CAR T cell fitness. Expansion, contractions, and persistence of CAR T cells is often limited after infusion. Bottom left: homing/penetration. CAR T cells have a limited ability to traffic to and penetrate solid tumors. Bottom right: microenvironment. The solid tumor microenvironment is hostile, limiting CAR T cell effector function.

Figure 2

Strategies to Overcome CAR T Cell Immunotherapy Roadblocks for Solid Tumors Summary of strategies that are discussed in detail in this review.

Figure 3

Immunosuppressive Solid Tumor Microenvironment Scheme of the solid tumor microenvironment that consists of (1) tumor vasculature; (2) stromal cells, including cancer-associated fibroblasts; (3) immunosuppressive cells, including myeloid cells, macrophages, and regulatory T cells (Tregs); (4) suppressive metabolites; (5) inhibitory ligands, including PD-1; and (6) suppressive cytokines. See text for additional details.