A bispecific T cell engager recruits both type 1 NKT and Vγ9Vδ2-T cells for the treatment of CD1d-expressing hematological malignancies.

Bispecific T cell engagers (bsTCEs) hold great promise for cancer treatment but face challenges due to the induction of cytokine release syndrome (CRS), on-target off-tumor toxicity, and the engagement of immunosuppressive regulatory T cells that limit efficacy. The development of Vγ9Vδ2-T cell engagers may overcome these challenges by combining high therapeutic efficacy with limited toxicity. By linking a CD1d-specific single-domain antibody (VHH) to a Vδ2-TCR-specific VHH, we create a bsTCE with trispecific properties, which engages not only Vγ9Vδ2-T cells but also type 1 NKT cells to CD1d ⁺ tumors and triggers robust proinflammatory cytokine production, effector cell expansion, and target cell lysis in vitro. We show that CD1d is expressed by the majority of patient MM, (myelo)monocytic AML, and CLL cells and that the bsTCE triggers type 1 NKT and Vγ9Vδ2-T cell-mediated antitumor activity against these patient tumor cells and improves survival in in vivo AML, MM, and T-ALL mouse models. Evaluation of a surrogate CD1d-γδ bsTCE in NHPs shows Vγ9Vδ2-T cell engagement and excellent tolerability. Based on these results, CD1d-Vδ2 bsTCE (LAVA-051) is now evaluated in a phase 1/2a study in patients with therapy refractory CLL, MM, or AML.
Competing Interests: Declaration of interests J.M.R., V.I.G., F.S.v.d.B., B.W., R.C.R., A.E.P.A., T.R., P.W.H.I.P., and H.J.v.d.V. are employees of LAVA Therapeutics, a company that develops bispecific gamma-delta T cell engagers, and own LAVA Therapeutics shares and/or stock options. R.L., T.D.d.G., P.W.H.I.P., and H.J.v.d.V. are named inventors on international patent application WO2020/060,405 ("Dual acting CD1d immunoglobulin"), which partially relates to the work described in this paper. T.D.d.G. is a consultant for and a shareholder of LAVA Therapeutics. A.P.K. is a consultant for LAVA Therapeutics. R.L., M.J., M.V., and I.d.W. were funded by a LAVA Therapeutics grant to Amsterdam UMC.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)