Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell–depleted stem cell transplantation

Shah, Nirali N.; Baird, Kristin; Delbrook, Cynthia; Fleisher, Thomas A.; Kohler, M. Eric; Rampertaap, Shakuntala; Lemberg, Kimberly; Hurley, Carolyn Katovich; Kleiner, David E.; Merchant, Melinda S.; Pittaluga, Stefania; Sabatino, Marianna; Stroncek, David F.; Wayne, Alan S.; Zhang, Hua; Fry, Terry J.; Mackall, Crystal L.

doi:10.1182/blood-2014-07-592881

Cited by 200 publications

(172 citation statements)

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“…57,58 Although the in vitro expansion, activation, and adoptive transfer of NK cells is an attractive therapeutic approach, early studies have already suggested the capability to invoke GVHD via donor T-cell activation in patients not receiving immune suppression. 59 Our study highlights the clinical need for recognition that the presence of GVHD precludes an effective NK-cell-dependent leukemia and pathogen-specific response that no doubt contributes to poor outcomes. The effective prevention of alloreactive T-cell responses and the consequent consumption of IL-15 is paramount to preventing this important innate immune deficiency and should be the focus of clinical studies.…”

Section: Discussionmentioning

confidence: 74%

GVHD prevents NK-cell–dependent leukemia and virus-specific innate immunity

Bunting

Varelias

Souza-Fonseca-Guimarães

et al. 2017

Blood

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Key Points• Donor T cells compete for IL-15 with NK cells during GVHD, resulting in profound defects in NK-cell reconstitution.• GVHD impairs NK-celldependent leukemia and pathogen-specific immunity.Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graftversus-host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Ra or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects.Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity. (Blood. 2017;129(5):630-642)

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Section: Discussionmentioning

confidence: 74%

GVHD prevents NK-cell–dependent leukemia and virus-specific innate immunity

Bunting

Varelias

Souza-Fonseca-Guimarães

et al. 2017

Blood

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“…NK cells have been traditionally recognized as possessing antitumour functions without causing GVHD 41. However, Shah NN et al reported that adoptive IL‐15/4‐1BBL‐activated NK cell infusion post‐HLA‐matched, T cell‐depleted transplantation contributed to acute GVHD 42. Therefore, the contribution of NK1 cells to the prognosis of chronic GVHD warrants further study.…”

Section: Discussionmentioning

confidence: 99%

Effect of the in vivo application of granulocyte colony‐stimulating factor on NK cells in bone marrow and peripheral blood

Han

et al. 2018

J Cellular Molecular Medi

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Granulocyte colony‐stimulating factor (G‐CSF) has been widely used in the field of allogeneic haematopoietic stem cell transplantation (allo‐HSCT) for priming donor stem cells from the bone marrow (BM) to peripheral blood (PB) to collect stem cells more conveniently. Donor‐derived natural killer (NK) cells have important antitumour functions and immune regulatory roles post‐allo‐HSCT. The aim of this study was to evaluate the effect of G‐CSF on donors' NK cells in BM and PB. The percentage of NK cells among nuclear cells and lymphocyte was significantly decreased and led to increased ratio of T and NK cells in BM and PB post‐G‐CSF in vivo application. Relative expansion of CD56bri NK cells led to a decreased ratio of CD56dim and CD56bri NK subsets in BM and PB post‐G‐CSF in vivo application. The expression of CD62L, CD54, CD94, NKP30 and CXCR4 on NK cells was significantly increased in PB after G‐CSF treatment. G‐CSF treatment decreased the IFN‐γ‐secreting NK population (NK1) dramatically in BM and PB, but increased the IL‐13‐secreting NK (NK2), TGF‐β‐secreting NK (NK3) and IL‐10‐secreting NK (NKr) populations significantly in BM. Clinical data demonstrated that higher doses of NK1 infused into the allograft correlated with an increased incidence of chronic graft‐vs‐host disease post‐transplantation. Taken together, our results show that the in vivo application of G‐CSF can modulate NK subpopulations, leading to an increased ratio of T and NK cells and decreased ratio of CD56dim and CD56bri NK cells as well as decreased NK1 populations in both PB and BM.

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“…Results have seemed most promising when there is evidence of persistence and expansion of the NK cells after infusion 130 . A recent study has reported severe GVHD in some cancer patients given T celldepleted allogeneic haemato poietic stem cell transplants infused with allogeneic NK cells pre-activated in vitro with IL-15 and TNFSF9 (also known as 4-1BBL) 132 . Although it is not known whether the GVHD was caused directly by the NK cells, or the NK cells induced a T cell-mediated GVHD response, this outcome was surprising given that NK cells have not been shown to cause GVHD in previous human clinical trials or in preclinical mouse models.…”

Section: Using Nk Cells For Cancer Therapymentioning

confidence: 99%