CD3‐T‐cell‐engager (TCE) therapies to overcome solid tumors: Beyond BiTEs

Abstract CD3‐T‐cell‐engager (TCE) therapies, such as bispecific T‐cell engagers (BiTEs), have achieved extraordinary success in treating hematological malignancies and have shown therapeutic effects comparable with those of chimeric antigen receptor (CAR)‐T therapies. However, solid tumors are challenging to treat with TCE therapies due to tumor heterogeneity, limited tumor enrichment, an immunosuppressive tumor microenvironment (TME), a lack of pre‐existing tumor‐infiltrating lymphocytes (TILs), serious on‐target off‐tumor toxicity, and so forth. Thanks to the increased understanding of resistance mechanisms and novel technologies, the next generation of TCE therapies for solid tumors is emerging. We focus on summarizing the latest progress in CD3‐based TCE therapies and discussing the future perspective of TCE therapeutic strategies against solid tumors. This perspective highlighted novel multitarget TCE therapies that integrated multiple functionalities to enhance antitumor efficacy while minimizing off‐target toxicity. Furthermore, TCE therapies also could be rationally combined with other antitumor therapeutics, including oncolytic viruses, CAR‐T cells, and immune checkpoint blockade. Moreover, TCEs should not be limited to redirecting polyclone T cells to tumor cells. The development of novel TCEs to bridge T cells and other cells in the TME is also promising. This perspective motivates the development of the new TCE therapies strategy to broaden the armamentarium of CD3‐TCE therapies and overcome solid tumors.