A novel pan-gamma-delta T cell engager platform for next-generation cancer therapeutics

Bispecific T cell engagers (TCEs) are potent immunotherapeutic molecules that redirect the body's T cells to kill tumor or pathogenic cells by bridging CD3 and tumor-associated antigen (TAA). Over the past decade, TCE-based therapies have achieved great success for the treatment of liquid tumors. However, although there is a multitude of TCEs with solid tumor targets in preclinical and clinical development, only one DLL3-targeting TCE was approved by FDA. For most TCEs targeting solid tumors, the main concern is on-target/off-tumor cytotoxicity, that is target organ toxicity due to redirection of T cells to normal tissues expressing the TAA. In addition, excessive release of cytokines may also translate to potentially life-threating cytokine release syndrome (CRS). To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges. Gamma-Delta T (gammadeltaT) cells can leverage both innate and adaptive immunity to combat target cells. Gamma-delta T cell engager (gammadeltaTCE) is a novel antitumor therapeutic to redirect gammadelta T cells to eliminate tumor or other pathogenic cells without pan T cell activation, therefore resulting in improved therapeutic index compare to pan T cell engager. To test this hypothesis, WuXi Biologics has developed a novel and unique pan-gammadelta TCE platform for the undruggable or hard-to-drug TAAs, that CD3 TCE can't target. Epidermal growth factor receptor (EGFR) is highly expressed in many solid tumors (e.g. non-small cell lung cancer and colorectal cancer) and low in normal tissues. EGFR has been clinically validated by multiple drug modalities, such as monoclonal antibodies and antibody-drug conjugates. However, EGFR x CD3 TCE, which may be the most powerful therapeutic modality, remains undruggable due to severe adverse effects of cytokine release and on-target/off-tumor toxicities. WuXi Biologics' EGFR-gammadeltaTCE is able to motivate diverse gammadelta T cell populations with equivalent activity, inducing significant expansion of gammadelta T cells without causing exhaustion. Compared with the clinical Vdelta1 and Vdelta2 benchmarks, WuXi Biologics' EGFR-gammadeltaTCE showed more efficient cytotoxicity against tumor cells, while sparing healthy cells and maintaining low cytokines. In in vivo antitumor studies of human colorectal cancer HCT116 xenograft models, the EGFR-gammadeltaTCE also exhibited superior antitumor efficacy than the clinical benchmarks. The studies support WuXi Biologics' EGFR-gammadeltaTCE as a promising novel therapeutic to target multiple solid tumors with EGFR expression and also demonstrate that WuXi Biologics' gammadeltaTCE platform has the potential to become best-in-class and can be applied to the undruggable or hard-to-drug TAAs.