Combining the best of two worlds: highly flexible chimeric antigen receptor adaptor molecules (CAR-adaptors) for the recruitment of chimeric antigen receptor T cells

Abstract

Chimeric antigen receptor (CAR)-engineered T cells have a proven efficacy for the treatment of refractory hematological B cell malignancies. While often accompanied by side effects, CAR-T technology is getting more mature and will become an important treatment option for various tumor indications. In this review, we summarize emerging approaches that aim to further evolve CAR-T cell therapy based on combinations of so-called universal or modular CAR-(modCAR-)T cells, and their respective adaptor molecules (CAR-adaptors), which mediate the crosslinking between target and effector cells. The activity of such modCAR-T cells is entirely dependent on binding of the respective CAR-adaptor to both a tumor antigen and to the CAR-expressing T cell. Contrary to conventional CAR-T cells, where the immunological synapse is established by direct interaction of CAR and membrane-bound target, modCAR-T cells provide a highly flexible and customizable development of the CAR-T cell concept and offer an additional possibility to control T cell activity.

Keywords: CAR-adaptor; Chimeric antigen receptor (CAR); adaptor molecule; adoptive T cell therapy; antibody; immunological synapse; universal CAR-T cells.

Figure 1.

Schematic representation of a second generation, conventional CAR-T cell. CAR-T cells target surface antigens directly in a major histocompatibility class-independent manner. They consist of an extracellular antigen recognition domain (ECD), conventionally a single chain variable fragment (scFv), which is linked via hinge region (hinge) to a transmembrane domain (TM), followed by an intracellular costimulatory domain (ICD) and a CD3ζ signaling domain.

Figure 2.

Indirect and flexible antigen targeting through CAR-adaptor molecules (CAR-adaptors). Depicted are the different designs of antigen-targeting CAR-adaptors that are used with a modular CAR (modCAR)-engineered effector cell. (a) IgG-tag-based CAR-adaptor | (b) IgG CAR-adaptor | (c) small molecule-based CAR-adaptor | (d) Fab-based CAR-adaptor | (e) scFv-based CAR-adaptor | (f) bispecific-based CAR-adaptor | (g) nanobody-based CAR-adaptor | (h) bivalent nanobody-based CAR-adaptor.

Figure 3.

Depicted is a modular CAR (modCAR) engineered effector cell with diverse ECDs able to target a CAR adaptor molecule (CAR-adaptor), here represented by an IgG. (i) scFv-ECD | (j): FcR-ECD | (k) and (l) monomeric and dimeric avidin-ECD require a biotinylated CAR-AM to enable antigen targeting | (m) leucine zipper.