Aldehyde Dehydrogenase Expression Drives Human Regulatory T Cell Resistance to Posttransplantation Cyclophosphamide

Kanakry, Christopher G.; Ganguly, Sudipto; Zahurak, Marianna; Bolaños-Meade, Javier; Thoburn, Christopher J.; Perkins, Brandy; Fuchs, Ephraim J.; Jones, Richard J.; Hess, Allan D.; Luznik, Leo

doi:10.1126/scitranslmed.3006960

Cited by 311 publications

(317 citation statements)

References 53 publications

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“…115 Donor T cells exposed to host antigens on day 0 were largely depleted, whereas non-alloreactive donor T cells, which divided more slowly in a lymphopenic environment, were relatively spared. 115 However, destruction of alloreactive donor T cells was necessary but not sufficient for PTCy-induced tolerance: in mouse models of MHCmatched alloBMT in which donor CD4 + T cells promote GVHD, as well as in xenograft models, donor T REG cells were necessary to prevent lethal GVHD after PTCy treatment, 116,117 an effect consistent with the results from skin allograft models. Donor T REG cells in both mouse and human models of alloBMT were resistant to PTCy-induced cytotoxicity owing to increased expression of aldehyde dehydrogenase, the enzyme primarily responsible for in vivo detoxification of cyclophosphamide, 118 upon alogeneic stimulation in a lymphopenic environment.…”

Section: Post-transplantation Cyclophosphamide Biological and Preclinsupporting

confidence: 71%

Erratum: Modern approaches to HLA-haploidentical blood or marrow transplantation.

Kanakry¹,

Fuchs²,

Luznik³

2015

Nat Rev Clin Oncol

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Allogeneic blood or bone-marrow transplantation (alloBMT) is a potentially curative treatment for a variety of haematological malignancies and nonmalignant diseases. Historically, human leukocyte antigen (HLA)-matched siblings have been the preferred source of donor cells owing to superior outcomes compared with alloBMT using other donors. Although only approximately onethird of patients have an HLA-matched sibling, nearly all patients have HLA-haploidentical related donors. Early studies using HLA-haploidentical alloBMT resulted in unacceptably high rates of graft rejection and graft-versus-host disease (GVHD), leading to high nonrelapse mortality and consequently poor survival. Several novel approaches to HLA-haploidentical alloBMT have yielded encouraging results with high rates of successful engraftment, effective GVHD control and favourable outcomes. In fact, outcomes of several retrospective comparative studies seem similar to those seen using other allograft sources, including those of HLA-matched-sibling alloBMT. In this Review, we provide an overview of the three most-developed approaches to HLA-haploidentical alloBMT: T-cell depletion with 'megadose' CD34 + cells; granulocyte colonystimulating factor-primed allografts combined with intensive pharmacological immunosuppression, including antithymocyte globulin; and high-dose, post-transplantation cyclophosphamide. We review the preclinical and biological data supporting each approach, results from major clinical studies, and completed or ongoing clinical studies comparing these approaches with other alloBMT platforms.

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Section: Post-transplantation Cyclophosphamide Biological and Preclinsupporting

confidence: 71%

Erratum: Modern approaches to HLA-haploidentical blood or marrow transplantation.

Kanakry¹,

Fuchs²,

Luznik³

2015

Nat Rev Clin Oncol

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“…Post-transplant Cy is an effective strategy for GVHD prevention with reduced impairment in immune reconstitution that is observed with more profound T-cell depletion strategies previously used in haploidentical HSCT. 27,31 In our small series, the rate of acute and chronic GVHD was low, and only one patient developed severe GVHD that needed secondary systemic therapy. The use of post transplant Cy for GVHD prophylaxis during haploidentical HSCT has been associated with relatively high rates of relapse in patients with hematologic malignancies, probably because of mitigation of the GVL effect.…”

Section: Discussionmentioning

confidence: 65%

Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study

Esteves

Bonfim

Pasqüini

et al. 2015

Bone Marrow Transplant

137

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Patients with refractory severe aplastic anemia (SAA) who lack a matched sibling or unrelated donor need new therapeutic approaches. Hematopoietic SCT (HSCT) using mismatched or haploidentical related donors has been used in the past, but was associated with a significant risk of GVHD and mortality. Recently, the use of post-transplant cyclophosphamide (Cy) has been shown to be an effective strategy to prevent GVHD in recipients of haploidentical HSCT, but the majority of reports have focused on patients with hematology malignancies. We describe the outcome of 16 patients who underwent haploidentical transplantation using a reduced-intensity conditioning regimen with post-transplant Cy. Stem cell sources were BM (N = 13) or PBSCs (N = 3). The rate of neutrophil engraftment was 94% and of platelet engraftment was 75%. Two patients had secondary graft failure and were successfully salvaged with another transplant. Three patients developed acute GVHD being grades 2-4 in two. Five patients have died and the 1-year OS was 67.1% (95% confidence interval: 36.5-86.4%). In our small series, the use of a reduced-intensity conditioning with post-transplant Cy in haploidentical BMT was associated with high rates of engraftment and low risk of GVHD in patients with relapsed/refractory SAA.

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“…16 Furthermore, CD4(+)CD45RA(− )Foxp3 (+hi) effector regulatory T cells express high levels of aldehyde dehydrogenase and appear to readily survive the use of high-dose CY and may contribute to the prevention of GVHD following Haplo-post-HCT-CY. 17 Based upon some of these observations, the group at Johns Hopkins University translated this approach into a clinical protocol of HaploD transplantation using a non-myeloablative conditioning regimen (pre-transplant fludarabine (150 mg/m 2 ), CY (29 mg/kg) and 2 Gy TBI, a T-replete BM graft followed by ptCY (50 mg/kg on d+3), MMF (day 4 to 35) and tacrolimus (day 4 to >50). 18 They demonstrated that donor engraftment without severe GVHD occurred in eight of ten patients treated on this regimen.…”

Section: Use Of Post-transplant Cy To Selectively Control Allo-reactimentioning

confidence: 99%

T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor

Bashey

Solomon

2014

Bone Marrow Transplant

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Availability of an HLA-identical sibling (MRD) or suitably matched unrelated donor (MUD) has historically been a limiting factor in the application of allogeneic hematopoietic transplantation. Although almost all patients have an HLA-haploidentical family donor, prior attempts at transplantation from such donors using T-cell replete grafts and conventional immunosuppression were associated with unacceptable rates of GVHD, and when stringent ex vivo T-cell depletion was used to control GVHD, rates of graft rejection and post-transplant infections were prohibitive. The recent approach to HLA-haploidentical donor transplantation developed in Baltimore that uses T-cell replete grafts and post-transplant CY (Haplo-post-HCT-CY) to control post-transplant allo-reactivity appears to have overcome many of the obstacles historically associated with haploidentical donor transplantation. In particular, TRM rates of o10% are usual and rapid reconstitution of immunity leads to a low rate of post-transplant infections and no post-tranplant lymphoproliferative disorders (PTLD), consistent with the hypothesis that post-transplant CY selectively depletes proliferating alloreactive T cells responsible for GVHD and graft rejection while preserving resting memory T cells essential for post-transplant immunologic recovery. In parallel trials using similar non-myeloablative conditioning regimens, Haplo-post-HCT-CY produced similar overall survival to double umbilical cord blood transplantation(DUCBT) in adult patients (62% vs 54%), with low rates of TRM (7% vs 24%), severe acute GVHD (0% vs 21%) and chronic GVHD (13% vs 25%). Furthermore, recent non-randomized comparisons adjusted for risk factors show that Haplo-post-HCT-CY achieve at least equivalent outcomes to conventional MRD and MUD transplants. Although most experience has been obtained using BM, emerging data suggest that a G-CSF mobilized PBSC graft can also safely be used for Haplo-post-HCT-CY. Haplo-post-HCT-CY also avoids the graft acquisition costs of DUCBT and MUDs and the cost of cell selection associated with T-depleted grafts. Although randomized comparisons will be forthcoming, Haplo-post-HCT-CY can already be considered a valid standard-of-care in patients who lack conventional donors thus extending the availability of allogeneic transplants to almost all patients. This donor source may also challenge the routine preference for a MUD in patients lacking an MRD.

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Aldehyde Dehydrogenase Expression Drives Human Regulatory T Cell Resistance to Posttransplantation Cyclophosphamide

Cited by 311 publications

References 53 publications

Erratum: Modern approaches to HLA-haploidentical blood or marrow transplantation.

Erratum: Modern approaches to HLA-haploidentical blood or marrow transplantation.

Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study

T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor

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