Zoledronic acid boosts γδ T-cell activity in children receiving αβ⁺T and CD19⁺cell-depleted grafts from an HLA-haplo-identical donor

Abstract

We demonstrated that γδ T cells of patients given HLA-haploidentical HSCT after removal of αβ T cells and CD19 B cells are endowed with the capacity of killing leukemia cells after treatment with zoledronic acid (ZOL). Thus, we tested the hypothesis that infusion of ZOL in patients receiving this type of graft may enhance γδ T-cell cytotoxic activity against leukemia cells. ZOL was infused every 28 d in 43 patients; most were treated at least twice. γδ T cells before and after ZOL treatments were studied in 33 of these 43 patients, till at least 7 mo after HSCT by high-resolution mass spectrometry, flow-cytometry, and degranulation assay. An induction of Vδ2-cell differentiation, paralleled by increased cytotoxicity of both Vδ1 and Vδ2 cells against primary leukemia blasts was associated with ZOL treatment. Cytotoxic activity was further increased in Vδ2 cells, but not in Vδ1 lymphocytes in those patients given more than one treatment. Proteomic analysis of γδ T cells purified from patients showed upregulation of proteins involved in activation processes and immune response, paralleled by downregulation of proteins involved in proliferation. Moreover, a proteomic signature was identified for each ZOL treatment. Patients given three or more ZOL infusions had a better probability of survival in comparison to those given one or two treatments (86% vs. 54%, respectively, = 0.008). Our data indicate that ZOL infusion in pediatric recipients of αβ T- and B-cell-depleted HLA-haploidentical HSCT promotes γδ T-cell differentiation and cytotoxicity and may influence the outcome of patients.

PMN-MDSC are a new target to rescue graft-versus-leukemia activity of NK cells in haplo-HSC transplantation

“…Unlike NK cells, γδT lymphocytes were mostly resistant to the inhibitory effect of PMN-MDSC (data not shown). Notably, patients given αβT cell-and B cell-depleted haplo-HSCT frequently received zoledronic acid that induces a marked γδT-cell expansion and also renders patient leukemia blasts more susceptible to the lytic activity of γδT lymphocytes [14,15]. Our present data suggest an important approach (i.e., removal of PNM-MDSC from the graft) to rescue NK-cell function for further improving the efficacy of αβT cell-and B cell-depleted haplo-HSCT.…”

αβ-T-cell-depleted haploidentical hematopoietic stem cell transplantation in children with chemorefractory acute myeloid leukemia

“…влияние ранней иммунореконституции и несовместимости по комплексу KiR. Одно из потенциальных преимуществ применения αβ-T-клеточной деплеции -ранняя иммунореконституция: восстановление естественных киллеров, γδ-и αβ-T-клеток происходит раньше, чем при использовании технологии позитивной селекции CD34+ клеток [7,14]. Мы оценили влияние раннего восстановления этих популяций лимфоцитов на основные исходы.…”

Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells

“…The most widely used method for activating and expanding TCR-γδ T-cells in vivo and ex vivo is through stimulation with IL-2 and aminobisphosphonates, such as Zoledronate, which preferentially expands the Vγ9Vδ2 subtype (8). However, post-HCT ZOL+IL-2 therapy fails to expand TCR-γδ cells in vivo to levels associated with increased survival in ∼58% of alloHCT patients (9), while the ex vivo expansion of Vγ9Vδ2 with ZOL+IL-2 for adoptive transfer therapy is sometimes unsuccessful due to low numbers of TCR-γδ T-cells in peripheral blood (10). It is important, therefore, to find new ways of mobilizing TCR-γδ T-cells to enrich peripheral blood hematopoietic stem cell grafts prior to transplant, and also to augment TCR-γδ responses to ZOL+IL-2 both in vivo and ex vivo (9,11).…”