Vγ2 x PD-L1, a Bispecific Antibody Targeting Both the Vγ2 TCR and PD-L1, Improves the Anti-Tumor Response of Vγ2Vδ2 T Cell

Abstract

The potent cytotoxic property of Vγ2Vδ2 T cells makes them attractive for adoptive T cell transfer therapy. The transfusing of the expanded Vγ2Vδ2 T cells into cancer patients shows well-tolerated, but the clinical response rates are required to be improved, implying that there is still an unmet efficacy with low toxicity for this novel anti-tumor therapy. In this study, we test the anti-tumor efficacy of a Y-body-based bispecific antibody (bsAb) Vγ2 x PD-L1 that preferentially redirects Vγ2Vδ2 T cells to combat PD-L1 positive tumor cells. With nanomolar affinity levels to Vγ2Vδ2 T cells and PD-L1+ tumor cells, Vγ2 x PD-L1 bridges a Vγ2Vδ2 T cell with a SKOV3 tumor cell to form a cell-to-cell conjugation. In a PD-L1-dependent manner, the bsAb elicits effective activation (CD25+CD69+), IFNγ releasing, degranulation (CD107a+), and cytokine production (IFNγ+ and TNFα+) of expanded Vγ2Vδ2 T cells. The activations of the Vγ2Vδ2 T cells eliminate PD-L1-expressing human cancer cell lines, including H1975, SKOV3, A375, H1299, and H2228 cells, but not PD-L1 negative cells including HEK-293 (293) cells and healthy PBMCs. Finally, we show that combining Vγ2 x PD-L1 with adoptively transferring Vγ2Vδ2 T cells inhibits the growth of existing tumor xenografts and increases the number of Vγ2Vδ2 T cells into the tumor bed. Vγ2 x PD-L1 represents a promising reagent for increasing the efficacy of adoptively transferred Vγ2Vδ2 T cells in the treatment of PD-L1 positive malignant tumors.

γδ T cells and the PD-1/PD-L1 axis: a love–hate relationship in the tumor microenvironment

“…To this end, scientists have devised a Y-body-based bispecific antibody (bsAb) known as the Vγ2 × PD-L1 antibody, which exhibits a selective affinity towards Vγ2Vδ2 T cells for the purpose of eliminating PD-L1 + tumor cells. The combination of Vγ2 × PD-L1 with adoptive metastatic Vγ2Vδ2 T cells has been demonstrated to impede the progression of established tumor xenografts and enhance the infiltration of Vγ2Vδ2 T cells into the TME [ 92 ]. Another EGFR-Vδ2 bispecific T-cell engager (bsTCE) can activate Vγ9Vδ2 T cells in the PB and tumor samples of EGFR + cancer patients.…”

γδ T cells and their clinical application in colon cancer

“…Vγ9-TCR-specific engagers binding to either CD123 ( 77 ) or HER2 ( 56 ) mediate cytotoxicity against tumor cells in acute myeloid leukemia and pancreatic adenocarcinomas, respectively. Moreover, they have the potential to enhance the efficacy of adoptively transferred γδ T cells ( 78 ). Lava Therapeutics is currently conducting two open-label phase I/IIa studies to assess the efficacy and safety of LAVA-051 ( 79 ), a humanized bispecific single-domain antibody that directly engages CD1d and the Vδ2 chain of Vγ9Vδ2 T cells in patients with relapsed/refractory chronic lymphocytic leukemia, multiple myeloma, and acute myeloid leukemia (NCT04887259) and LAVA-1207, which activates Vγ9Vδ2 T cells upon crosslinking to prostate-specific membrane antigen (PSMA) in patients with metastatic castration-resistant prostate cancer (NCT05369000).…”

Vγ9Vδ2 T-cell immunotherapy in blood cancers: ready for prime time?

“…This strategy allows the manufacturing and expansion from healthy donors of huge numbers of highly pure Vγ9Vδ2 T cells ( 117 ). The cytotoxic activity of adoptively transferred Vγ9Vδ2 T cells can be strengthened with mAbs to relieve ICP/ICP-L-dependent immune suppression ( 122 , 123 ), and/or with agonistic anti-BTN3A 20.1 mAb or BiTes to boost antitumor immune effector functions ( 124 ).…”