Leveraging Vγ9Vδ2 T cells against prostate cancer through a VHH-based PSMA-Vδ2 bispecific T cell engager.

Vγ9Vδ2 T cells constitute a homogeneous effector T cell population that lyses tumors of different origin, including the prostate. We generated a bispecific T cell engager (bsTCE) to direct Vγ9Vδ2 T cells to PSMA ⁺ prostate cancer (PCa) cells. The PSMA-Vδ2 bsTCE triggered healthy donor and PCa patient-derived Vγ9Vδ2 T cells to lyse PSMA ⁺ PCa cell lines and patient-derived tumor cells while sparing normal prostate cells and enhanced Vγ9Vδ2 T cell antigen cross-presentation to CD8 ⁺ T cells. Vγ9Vδ2 T cell expressed NKG2D and DNAM-1 contributed to Vγ9Vδ2 T cell activation and tumor lysis at low PSMA-Vδ2 bsTCE concentrations. In vivo models confirmed the antitumor efficacy of the bsTCE and demonstrated a half-life of 6-7 days. Tissue-cross reactivity analysis was in line with known tissue distribution of PSMA and Vγ9Vδ2 T cells. Together these data show the PSMA-Vδ2 bsTCE to represent a promising anti-tumor strategy and supports its ongoing evaluation in a phase 1/2a clinical trial in therapy refractory metastatic castration-resistant PCa.
Competing Interests: L.A.K., M.V.,and J.K. are/were funded by Lava Therapeutics NV. T.R., R.C.R., A.E.P.A., P.W.H.I.P., T.D.d.G.,and H.J.v.d.V. own Lava Therapeutics NV shares. V.I.-G., I.B., R.C.R., D.L.H., T.R., A.E.P.A., P.W.H.I.P., and H.J.v.d.V. are/were employees of Lava Therapeutics NV. T.D.d.G.is scientific advisor to Lava Therapeutics NV. Patent registration related to this work: Antibodies that bind PSMA and gamma-delta T cell receptors, Lava Therapeutics NV, WO2022008646A1, 2022-01-13.
(© 2024 The Authors.)