Disease remission is successfully induced in the majority of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), but is generally not sustained without stem cell transplantation. Adoptive immunotherapy offers an attractive option to consolidate AML remission. Here, we hypothesized that ex-vivo expanded Vg9Vd2 T-cells will mediate a therapeutically beneficial graft versus leukemia (GvL) effect in this disease.
Peripheral blood mononuclear cells from healthy donors and from patients with AML were activated in-vitro using zoledronic acid and a cytokine cocktail, containing IL-2. As a result, we observed an average 200-fold expansion of Vg9Vd2 T-cells from AML patients, over 15 days. Such expansion was only observed in patients without circulating AML blasts. Expanded patient-derived Vg9Vd2 T-cells exhibited a less differentiated phenotype than cells from healthy donors, indicated by higher expression of CD62L, CCR7 and CD27. A four hour Annexin V cytotoxicity assay using KG-1 and U937 leukemic cells showed that these Vg9Vd2 T-cells were cytotoxic and produced nanogram amounts of interferon-g; (IFN-g).
In a parallel approach, we investigated feasibility of developing a universal allogeneic Vg9Vd2 T-cell therapy. Feasibility of this approach has been demonstrated in a small trial in which haploidentical donor-derived Vg9Vd2 T-cells were safely infused and achieved an efficacy signal in patients with advanced haematological diseases. We have recently developed a novel method to expand Vg9Vd2 T-cells from healthy donors ex-vivo (“Method 2 (M2)” cells – patent protected), which improves their expansion over 2 weeks to 1700 fold. Cytotoxicity data shows that M2 cells destroy luciferase-expressing U937 and KG-1 target cells at 2-3 fold enhanced efficiency, accompanied by 2-3.5-fold increased IFN-g; release when compared to cells expanded using conventional approaches. Furthermore, M2 cells can achieve serial killing of AML cell lines through up to 4 cycles of re-stimulation. Treatment of SCID-Beige mice with an established U937 leukemic burden is also more effective using M2 expanded Vg9Vd2 T-cells, particularly when combined with zoledronic acid. Together these data highlight the promise of Vg9Vd2 T-cell immunotherapy of AML.
Citation Format: Ana C. Parente-Pereira, Lynsey M. Whilding, Pramila Krishnamurthy, Richard Beatson, Tomasz Zabinski, Linda Barber, Farzin Farzaneh, Ghulam Mufti, John Maher. Immunotherapy of acute myeloid leukemia using Vg9Vd2 T-cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B124.
- ©2016 American Association for Cancer Research.