At the Bench: Preclinical rationale for exploiting NK cells and γδ T lymphocytes for the treatment of high-risk leukemias

Norell, Håkan; Moretta, Alessandro; Silva‐Santos, Bruno; Moretta, Lorenzo

doi:10.1189/jlb.0613312

Cited by 39 publications

(36 citation statements)

References 234 publications

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“…Innate immune cells, notably NK cells and gd T cells, are of particular interest on account of their ability to kill hematological 2,3 or solid tumor cells 4 without inducing GvHD. 5,6 The anti-leukemic role of gd T cells was suggested by a correlation between Vd1 T cells expansion and prognosis following AHSCT. 7,8 Aside from Vd1 T cells, Vg9Vd2 T cells, the main circulating subset, account for 1-10% of human T lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

et al. 2016

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Given their recognized ability to kill acute myeloid leukemia (AML) blasts both in vitro and in vivo, Vg9Vd2 T cells are of growing interest in the design of new strategies of immunotherapy. We show that the Butyrophilin3A (BTN3A, CD277) subfamily is a critical determinant of Vg9Vd2 TCR-mediated recognition of human primary AML blasts ex vivo. Moreover, anti-BTN3A 20.1 agonist monoclonal antibodies (mAbs) can trigger BTN3A on AML blasts leading to further enhanced Vg9Vd2 T cell-mediated killing, but this mAb had no enhancing effect upon NK cell-mediated killing. We show that monocytic differentiation of primary AML blasts accounts for their AminoBisphosphonate (N-BP)-mediated sensitization to Vg9Vd2 T cells. In addition, anti-BTN3A 20.1 mAbs could specifically sensitize resistant blasts to Vg9Vd2 T cells lysis and overcome the poor effect of N-BP treatment on those blasts. We confirmed the enhancement of Vg9Vd2 T cells activity by anti-BTN3A 20.1 mAb using a human AML xenotransplantation mouse model. We showed that anti-BTN3A 20.1 mAb combined with Vg9Vd2 T cells immunotherapy could increase animal survival and decrease the leukemic burden in blood and bone marrow. These findings could be of great interest in the design of new immunotherapeutic strategies for treating AML.

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Section: Introductionmentioning

confidence: 99%

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

et al. 2016

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“…Two basic KIR haplotypes can be found in humans: the group A haplotype, which has a fixed number of genes encoding inhibitory receptors (with the exception of the activating receptor KIR2DS4), and the group B haplotypes, which have variable gene content and 1 or more of the B-specific genes: KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5, KIR2DL2, and KIR2DL5. 1,7,8 Among haplotype B individuals, a KIR B-content score can further be established 8 on the basis of the number of centromeric and telomeric KIR B haplotype motifs. Cooley et al recently reported a reduced relapse risk in adults with acute myeloid leukemia, but not in those with ALL, given allogeneic HSCT from unrelated KIR haplotype B donors.…”

Section: Introductionmentioning

confidence: 99%

KIR B haplotype donors confer a reduced risk for relapse after haploidentical transplantation in children with ALL

Oevermann

Michaelis

Mezger

et al. 2014

Blood

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131

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Key Points• KIR haplotype B donors and high KIR B content score confer better protection against relapse after HLAhaploidentical transplantation in pediatric acute lymphoblastic leukemia.• Haploidentical donor selection criteria for childhood acute lymphoblastic leukemia should include KIR haplotype and KIR B-content score.We analyzed the influence of donor killer-cell immunoglobulin-like receptor (KIR) gene haplotypes on the risk for relapse and the probability of event-free survival (EFS) in children with acute lymphoblastic leukemia who received human leukocyte antigenhaploidentical transplantation of ex vivo T-cell-depleted peripheral blood stem cells. The KIR gene haplotype was evaluated in 85 donors, and the KIR B content score was determined in the 63 KIR haplotype B donors. Patients transplanted from a KIR haplotype B donor had a significantly better EFS than those transplanted from a KIR haplotype A donor (50.6% vs 29.5%, respectively; P 5 .033). Moreover, a high donor KIR B-content score was associated with a significantly reduced risk for relapse (Log-rank test for trend, P 5 .026). These data indicate that KIR genotyping should be included in the donor selection algorithm for haploidentical transplantation in children with acute lymphoblastic leukemia with the aim of choosing, whenever possible, a KIR haplotype B donor with a high KIR B-content score. (Blood. 2014;124(17):2744-2747

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“…Although several studies have suggested beneficial roles of γδ T cells in the context of hematopoietic cell transplantation, reports of clinical experiences are still very limited. 6,[10][11][12][13][14][15] There have been several reports on HHCT in pediatric patients. 4,5,7,[16][17][18] In our current study, all 42 patients achieved stable engraftment early post transplant at a median of 10 days.…”

Section: Discussionmentioning

confidence: 99%

Haploidentical HCT using an αβ T-cell-depleted graft with targeted αβ+ cells by add-back after a reduced intensity preparative regimen containing low-dose TBI

Koh

et al. 2016

Bone Marrow Transplant

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Between 2012 and 2015, 42 pediatric patients underwent haploidentical hematopoietic cell transplantation using an αβ + T-cell-depleted graft with targeted αβ cells at 1-5 × 10 5 /kg by add-back; 31 had hematologic malignancy (HM), 8 had non-malignant disease (NM) and 3 had solid tumors. All patients received uniform reduced-intensity conditioning with fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin and low-dose TBI. All 42 patients achieved neutrophil engraftment at a median of 10 days. The cumulative incidences (CIs) of ⩾ grade II and ⩾ grade III acute GvHD were 31 ± 7.1% (SE) and 12 ± 5.0%, respectively, and 1-year CI of chronic GvHD was 15 ± 5.8%. One patient died of CMV pneumonia, leading to transplant-related mortality (TRM) of 2.6 ± 2.5%. Sixteen patients relapsed and 11 died of disease. At a median follow-up of 19 months (range, 5-43 months), the estimated 2-year event-free survival for NM and HM were 88 ± 11.7 and 50 ± 10.1%, respectively. Our study demonstrated that haploidentical hematopoietic cell transplantation after ex vivo depletion of αβ + T cells with targeted dose noticeably reduced the graft failure rate and TRM in pediatric patients and could be applied to patients lacking a suitable related or unrelated donor. While αβ + T cells are known to be associated with the initiation of GvHD, γδ + T cells can enhance immune reconstitution and are not implicated in GvHD. 6 Recently, we reported our experience with HHCT using a CD3-depleted graft. 7 Since 2012, we have initiated HHCT using ex vivo depletion of αβ + T cells with targeted αβ cells at 1-5 × 10 5 /kg after add-back. Here, we report our prospective results using αβ-depleted grafts in HHCT for children and adolescents with malignant or non-malignant disease.

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At the Bench: Preclinical rationale for exploiting NK cells and γδ T lymphocytes for the treatment of high-risk leukemias

Cited by 39 publications

References 234 publications

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

KIR B haplotype donors confer a reduced risk for relapse after haploidentical transplantation in children with ALL

Haploidentical HCT using an αβ T-cell-depleted graft with targeted αβ+ cells by add-back after a reduced intensity preparative regimen containing low-dose TBI

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