Chimeric Antigen Receptor-Modified T Cells and T Cell-Engaging Bispecific Antibodies: Different Tools for the Same Job

Abstract

Purpose of review: Both chimeric antigen receptor (CAR) T cells and T cell-engaging antibodies (BiAb) have been approved for the treatment of hematological malignancies. However, despite targeting the same antigen, they represent very different classes of therapeutics, each with its distinct advantages and drawbacks. In this review, we compare BiAb and CAR T cells with regard to their mechanism of action, manufacturing, and clinical application. In addition, we present novel strategies to overcome limitations of either approach and to combine the best of both worlds.

Recent findings: By now there are multiple approaches combining the advantages of BiAb and CAR T cells. A major area of research is the application of both formats for solid tumor entities. This includes improving the infiltration of T cells into the tumor, counteracting immunosuppression in the tumor microenvironment, targeting antigen heterogeneity, and limiting off-tumor on-target effects. BiAb come with the major advantage of being an off-the-shelf product and are more controllable because of their half-life. They have also been reported to induce less frequent and less severe adverse events. CAR T cells in turn demonstrate superior response rates, have the potential for long-term persistence, and can be additionally genetically modified to overcome some of their limitations, e.g., to make them more controllable.

Keywords: Adoptive T cell therapy; Bispecific antibody; Cancer; Chimeric antigen receptor; Immunotherapy; T cell redirection.

Fig. 1

Schematic presentation of the interaction between T cells and tumor cells via a TCR, a BiAb, a CAR, and a SAR in combination with a BiAb. a A CD8⁺ T cell recognizes a tumor cell presenting a peptide from a tumor antigen on MHC class I via its TCR. b A BiAb mediates T cell recognition of a tumor cell by binding to both an antigen on the T cell surface, most commonly CD3, and a tumor cell surface antigen. c A T cell genetically modified to express a CAR binds a surface antigen expressed on the tumor cell via the scFv domain of the CAR in an MHC-independent manner. d A SAR-transduced T cell interacts with a tumor cell via a BiAb binding the SAR extracellular domain and a tumor cell surface antigen. BiAb, T cell redirecting bispecific antibody; CAR, chimeric antigen receptor; SAR, synthetic agonistic receptor; TCR, T cell receptor