Biology and Clinical Evaluation of T/NK Cell Engagers

Bispecific engagers are cancer immunotherapeutics that incorporate at least two antigen recognition domains and engager both a tumor-associated antigen and an immune effector cell surface molecule to facilitate targeted antitumor activity. This strategy is most advanced for CD19+ B cell malignancies, where the CD19xCD3 bispecific T cell engager (BiTE) blinatumomab has achieved FDA approval. However, efforts are underway to expand the application of this technology to other malignancies. This chapter reviews design strategies to decrease immunogenicity, alter kinetics, enhance effector function, optimize antigen recognition, and direct specific assembly. Additionally, we explore alternative immune effector cell platforms and delivery methods. We describe the landscape of ongoing clinical studies of bispecific T cell and natural killer cell engagers for hematologic malignancies and solid tumors. As the clinical translation of bispecific immune cell engagers continues to advance, key additional considerations include the impact of the host immune environment, integration with other immune and conventional therapies, and mitigation of toxicities.KeywordsBispecific antibodyBispecific natural killer cell engager (BiKE)Bispecific T cell engager (BiTE)Cancer immunotherapyTrispecific killer engagers (TriKE)Dual affinity retargeting protein (DART)DuobodyDiabodyImmune-mobilizing monoclonal T cell receptor against cancer (ImmTAC)Monoclonal antibody