Engineering for Success: Approaches to Improve Chimeric Antigen Receptor T Cell Therapy for Solid Tumors

Abstract

While impressive clinical responses have been observed using chimeric antigen receptor (CAR) T cells targeting CD19+ hematologic malignancies, limited clinical benefit has been observed using CAR T cells for a variety of solid tumors. Results of clinical studies have highlighted several obstacles which CAR T cells face in the context of solid tumors, including insufficient homing to tumor sites, lack of expansion and persistence, encountering a highly immunosuppressive tumor microenvironment, and heterogeneous antigen expression. In this review, we review clinical outcomes and discuss strategies to improve the antitumor activity of CAR T cells for solid tumors.

Fig. 1

Antigen recognition mechanism of chimeric antigen receptors (CARs). a Antigens are processed within tumor cells and the major histocompatibility complex (MHC) presents antigenic peptides on the surface of tumor cells. T cells recognize antigens by an interaction with the T cell receptor (TCR) and peptide/MHC complex. b CAR T cells recognize cell-surface antigens on tumor cells in an unprocessed manner independent of MHC. ER endoplasmic reticulum

Fig. 2

Second-generation chimeric antigen receptor (CAR) design. While in conventional antigen recognition (signal 1) and co-stimulation (signal 2) are separated, second-generation CARs simultaneously transmit signals 1 and 2. APC antigen-presenting cell, MHC major histocompatibility complex, TCR T cell receptor

Fig. 3

Overcoming obstacles using chimeric antigen receptor (CAR) T cells for the treatment of solid tumors. Various approaches have been developed to enhance CAR T cell function in the context of solid tumors. Starting at the top of the figure and proceeding counter clockwise, these include (i) optimizing CAR design by using 4-1BB co-stimulation in cis or trans; (ii) expressing signal converters or dominant negative receptors; (iii) improving homing to tumors by expression of distinct chemokine receptors; (iv) promoting expansion and persistence of infused T cells using cytokines or cytokine receptors; (v) overcoming antigen heterogeneity or antigen loss by expression of CARs targeting two tumor antigens; (vi) selecting T cell subsets for genetic modification; and/or (vii) enhancing their safety. CCR C-C chemokine receptor, IL interleukin, T_CM central memory T cells, T_SCM memory stem T cells, tEGFR truncated epidermal growth factor receptor, TGFβR transforming growth factor β receptor, TLR4 Toll-like receptor 4

Fig. 4

Designing chimeric antigen receptors (CARs) to prevent toxicities. Several strategies have been developed to tune CAR activity. Four examples are illustrated (from left to right): (i) signals 1 and 2 can be split on two CARs with different antigen recognition domains, limiting full CAR T cell activation to sites, which express both antigens; (ii) the antigen recognition and signaling domains are encoded by two molecules that also contain a heterodimerizer domain under the control of a small dimerizer molecule; (iii) CAR expression can be linked to the presence of a second antigen; and (iv) CAR expression can be induced by a small molecule