# Donor-Derived Vγ9Vδ2 T Cells for Acute Myeloid Leukemia: A Promising “Off-the-Shelf” Immunotherapy Approach

## TL;DR

Donor-derived Vγ9Vδ2 T cells show strong potential as a new immunotherapy for acute myeloid leukemia, even in cases resistant to existing drugs.

## Contribution

Demonstrates the therapeutic potential of donor-derived Vγ9Vδ2 T cells in treating venetoclax-resistant AML using in vitro and in vivo models.

## Key findings

- Donor-derived Vγ9Vδ2 T cells efficiently induce apoptosis in AML cells in vitro.
- Treatment with Vγ9Vδ2 T cells significantly prolonged survival in AML xenograft mouse models.
- Vγ9Vδ2 T cells remain effective against venetoclax-resistant AML and work synergistically with venetoclax.

## Abstract

Donor-derived Vγ9Vδ2 T cells demonstrate potent anti-leukemic activity both in vitro and in vivo, offering a promising immunotherapeutic approach for acute myeloid leukemia (AML). These γδ T cells efficiently induce apoptosis in AML cells in vitro, highlighting their direct cytotoxic potential. In an aggressive AML xenograft mouse model, treatment with donor-derived Vγ9Vδ2 T cells significantly prolonged survival, indicating their therapeutic relevance in a clinically challenging setting. Importantly, these cells remain effective against venetoclax-resistant AML; in vivo studies further show that Vγ9Vδ2 T cells extend survival in mouse survival with or without venetoclax. These findings suggest the therapeutic potential of harnessing donor-derived Vγ9Vδ2 T cells as a novel strategy to overcome drug resistance and improve outcomes in AML, including in patients with limited responses to existing therapies.

Background: Venetoclax-based combination therapies have provided treatment options for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. However, venetoclax resistance is common, and for such patients, the prognosis is dismal, and treatment approaches with different mechanisms of action are urgently needed. γδ T cells are a promising candidate owing to their good safety profile and cytotoxic effects in various types of cancers but are mostly unstudied in AML. Methods: Here we used flow cytometry to profile the subtype and memory phenotype of peripheral blood γδ T cells in AML patients and investigate the feasibility of using donor-derived Vγ9Vδ2 T cells to treat AML as both a single agent and in combination with venetoclax. Additionally, we used bioluminescence imaging to examine the effect of donor-derived Vγ9Vδ2 T cells on AML xenograft models alone and in combination with venetoclax. Results: We observed that Vδ2 T cells were less abundant and the TEMRA (terminally differentiated effector memory) phenotype was more prevalent as compared with that of healthy donors, suggesting that replenishing patients with Vδ2 T cells may be an effective treatment option. We found that donor-derived Vγ9Vδ2 T cells that Vγ9Vδ2 T cells efficiently induced apoptosis in AML cells from eight cell lines and three primary cultures in an effector-to-target cell ratio-dependent manner. Moreover, Vγ9Vδ2 T cells showed potent cytotoxicity against the venetoclax-resistant OCI-AML3 cell line and remained potent in the presence of venetoclax. Treatment with Vγ9Vδ2 T cells significantly extended survival in two AML xenograft models established with the aggressive Molm-13 and the venetoclax-resistant OCI-AML3 cell lines. An additive effect of venetoclax and Vγ9Vδ2 T cells was observed in the latter model. Conclusions: Overall, these findings suggest Vγ9Vδ2 T cells as a promising “off-the-shelf” immunotherapy approach for AML patients, especially for patients with venetoclax-resistant disease.