CARs: Beyond T Cells and T Cell-Derived Signaling Domains

Abstract

When optimizing chimeric antigen receptor (CAR) therapy in terms of efficacy, safety, and broadening its application to new malignancies, there are two main clusters of topics to be addressed: the CAR design and the choice of transfected cells. The former focuses on the CAR construct itself. The utilized transmembrane and intracellular domains determine the signaling pathways induced by antigen binding and thereby the cell-specific effector functions triggered. The main part of this review summarizes our understanding of common signaling domains employed in CARs, their interactions among another, and their effects on different cell types. It will, moreover, highlight several less common extracellular and intracellular domains that might permit unique new opportunities. Different antibody-based extracellular antigen-binding domains have been pursued and optimized to strike a balance between specificity, affinity, and toxicity, but these have been reviewed elsewhere. The second cluster of topics is about the cellular vessels expressing the CAR. It is essential to understand the specific attributes of each cell type influencing anti-tumor efficacy, persistence, and safety, and how CAR cells crosstalk with each other and bystander cells. The first part of this review focuses on the progress achieved in adopting different leukocytes for CAR therapy.

The Landscape of CAR-T Cell Clinical Trials against Solid Tumors—A Comprehensive Overview

“…Future clinical trials should be focused on testing new CAR formats. This not only includes testing new extracellular antigen-binding domains, but also formats increasing the safety of CAR-T-cell usage (e.g., bi-specific CARs, or split CARs) [250], and new intracellular signaling domains [251]. Furthermore, new vehicles for CARs [251,252] hold great promise for broadening the applicability.…”

“…This not only includes testing new extracellular antigen-binding domains, but also formats increasing the safety of CAR-T-cell usage (e.g., bi-specific CARs, or split CARs) [ 250 ], and new intracellular signaling domains [ 251 ]. Furthermore, new vehicles for CARs [ 251 , 252 ] hold great promise for broadening the applicability. For example, the possibility of the off-the-shelf use of CAR-NK cells [ 253 ] or allogeneic CAR-T cells [ 254 ] can reduce costs for CAR-cell therapy and make it affordable for many more patients.…”

Current Status of CRISPR/Cas9 Application in Clinical Cancer Research: Opportunities and Challenges

“…Such tumor-targeting T cells have attracted a lot of interest. CARs consist of an extracellular domain that identifies target surface antigens, and an intracellular T cell signaling domain that triggers CAR-T cell activation [ 24 ]. A new generation of CAR-T cells has built-in co-stimulatory intracellular domains that allow expansion, proliferation and survival of T cells [ 25 , 26 ].…”

Nucleic Acid-Based Approaches for Tumor Therapy

“…The first generation of CARs contained only CD3 (ζ or γ chain) signaling motifs, which are able to activate murine CTL hybridoma cells, modified with chimeric genes for surface receptors, e.g., to trigger IL-2 secretion, but these may be inactivated by tumors [ 274 ]. The second generation of CARs was equipped in addition with a co-stimulatory domain, and the third generation possessed more than one co-stimulatory domain [ 275 ].…”