A Bispecific gd T-cell Engager Targeting EGFR Activates a Potent Vg9Vd2 T cell-Mediated Immune Response against EGFR-Expressing Tumors

Vy9V82 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing Vy9V82 T cells to EGFR-expressing tumors. An EGFR-V82 bispecific T-cell engager (bsTCE) was generated, and its capacity to activate Vy9V82 T cells and trigger antitumor activity was tested in multiple in vitro, in vivo, and ex vivo models. Studies to explore safety were conducted using cross-reactive surrogate engagers in nonhuman primates (NHP). We found that Vy9V82 T cells from peripheral blood and tumor specimens of patients with EGFR thorn cancers had a distinct immune checkpoint expres-sion profile characterized by low levels of PD-1, LAG-3, and TIM-3. Vy9V82 T cells could be activated by EGFR-V82 bsTCEs to mediate lysis of various EGFR thorn patient-derived tumor samples,and substantial tumor growth inhibition and improved survival were observed in in vivo xenograft mouse models using peripheral blood mononuclear cells (PBMC) as effector cells. EGFR-V82 bsTCEs exerted preferential activity toward EGFR thorn tumor cells and induced downstream activation of CD4 thorn and CD8 thorn T cells and natural killer (NK) cells without concomitant activation of suppressive regulatory T cells observed with EGFR-CD3 bsTCEs. Administration of fully cross-reactive and half-life extended surrogate engagers to NHPs did not trigger signals in the safety parameters that were assessed. Considering the effector and immune-activating properties of Vy9V82 T cells, the preclinical efficacy data and acceptable safety profile reported here provide a solid basis for testing EGFR-V82 bsTCEs in patients with EGFR thorn malignancies.