Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells

Ritacco, Caroline; Köse, Murat Cem; Courtois, Justine; Canti, Lorenzo; Beguin, Charline; Dubois, Sophie; Vandenhove, Benoît; Servais, Sophie; Caers, Jo; Béguin, Yves; Ehx, Grégory; Baron, Frédéric

doi:10.1016/j.isci.2023.106085

Cited by 10 publications

(11 citation statements)

References 62 publications

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“…A key goal of alloHSCT in people with blood cancers is the establishment of GVL immunity and to ensure any GVHD prophylaxis does not compromise this effect [2]. PTCy has been shown recently not to compromise GVL immunity in humanised NSG mice [27], but the impact of P2X7 antagonism on this effect in this mouse model has not been reported. To compare the impact of PTCy with BBG on GVL immunity, NSG mice were injected i.p.…”

Section: Ptcy With Bbg Does Not Compromise Gvl Immunitymentioning

confidence: 95%

Post-Transplant Cyclophosphamide Combined with Brilliant Blue G Reduces Graft-versus-Host Disease without Compromising Graft-versus-Leukaemia Immunity in Humanised Mice

Cuthbertson,

Button,

Sligar

et al. 2024

IJMS

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Allogeneic haematopoietic stem cell transplantation (HSCT) leads to the establishment of graft-versus-leukaemia (GVL) immunity, but in many cases also results in the development of graft-versus-host disease (GVHD). This study aimed to determine if P2X7 antagonism using Brilliant Blue G (BBG) could improve the beneficial effects of post-transplant cyclophosphamide (PTCy) in a humanised mouse model of GVHD, without comprising GVL immunity. NOD.Cg-Prkdcscid Il2rgtm1Wjl (NSG) mice were injected with human peripheral blood mononuclear cells (PBMCs) (Day 0), then with cyclophosphamide (33 mg/kg) on Days 3 and 4, and with BBG (50 mg/kg) (or saline) on Days 0–10. PTCy with BBG reduced clinical GVHD development like that of PTCy alone. However, histological analysis revealed that the combined treatment reduced liver GVHD to a greater extent than PTCy alone. Flow cytometric analyses revealed that this reduction in liver GVHD by PTCy with BBG corresponded to an increase in human splenic CD39+ Tregs and a decrease in human serum interferon-γ concentrations. In additional experiments, humanised NSG mice, following combined treatment, were injected with human THP-1 acute myeloid leukaemia cells on Day 14. Flow cytometric analyses of liver CD33+ THP-1 cells showed that PTCy with BBG did not mitigate GVL immunity. In summary, PTCy combined with BBG can reduce GVHD without compromising GVL immunity. Future studies investigating P2X7 antagonism in combination with PTCy may lead to the development of novel treatments that more effectively reduce GVHD in allogeneic HSCT patients without promoting leukaemia relapse.

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Section: Ptcy With Bbg Does Not Compromise Gvl Immunitymentioning

confidence: 95%

Post-Transplant Cyclophosphamide Combined with Brilliant Blue G Reduces Graft-versus-Host Disease without Compromising Graft-versus-Leukaemia Immunity in Humanised Mice

Cuthbertson,

Button,

Sligar

et al. 2024

IJMS

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“…After establishing a humanised mouse model of GVL, we next aimed to examine whether the GVL response was maintained following treatment with PTCy at days 3 and 4. PTCy has been shown to reduce GVHD in a humanised mouse model 12,23,30 but studies examining the impact of PTCy on GVL immunity and the mechanisms behind GVL responses are limited.…”

Section: Ptcy Reduces Weight Loss and Prolongs Time To Gvhd Onset In ...mentioning

confidence: 99%

Graft‐versus‐leukaemia immunity is retained following treatment with post‐transplant cyclophosphamide alone or combined with tocilizumab in humanised mice

Sligar,

Reilly,

Cuthbertson

et al. 2024

Clin & Trans Imm

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ObjectivesDonor haematopoietic stem cell transplantation treats leukaemia by inducing graft‐versus‐leukaemia (GVL) immunity. However, this benefit is often mitigated by graft‐versus‐host disease (GVHD), which is reduced by post‐transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity.MethodsNOD‐scid‐IL2Rγnull mice were injected with 2 × 107 human peripheral blood mononuclear cells (hPBMCs) on day 0 and with 1 × 106 THP‐1 acute myeloid leukaemia cells on day 14. In subsequent experiments, mice were also injected with PTCy (33 mg kg−1) or Dulbecco's phosphate buffered saline (PBS) on days 3 and 4, alone or combined with TOC or control antibody (25 mg kg−1) twice weekly for 28 days. Clinical signs of disease were monitored until day 42.ResultsMice with hPBMCs from three different donors and THP‐1 cells showed similar survival, clinical score and weight loss. hCD33+ leukaemia cells were minimal in mice reconstituted with hPBMCs from two donors but present in mice with hPBMCs from a third donor, suggesting donor‐specific GVL responses. hPBMC‐injected mice treated with PTCy alone or combined with TOC (PTCy + TOC) demonstrated prolonged survival compared to control mice. PTCy alone and PTCy + TOC‐treated mice with hPBMCs showed minimal hepatic hCD33+ leukaemia cells, indicating sustained GVL immunity. Further, the combination of PTCy + TOC reduced histological damage in the lung and liver.ConclusionCollectively, this research demonstrates that PTCy alone or combined with TOC impairs GVHD without compromising GVL immunity.

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“…Moreover, the PTCy-mediated tolerance induction process seems to be dependent on donor Treg cells, as mice depleted of Foxp3 + Treg either before or after PTCy treatment exhibited accelerated acute GVHD development ( 66 ). However, studies in humanized mouse models did not find the presence of Treg mandatory for PTCy-induced GVHD inhibition, as PTCy significantly mitigated the xenogeneic GVHD even when human PBMC depleted of CD25 + cells were infused ( 67 ). On the other hand, mice receiving untouched PBMC showed improved survival rates than those in which Treg were depleted.…”

Section: Enhancing the Gvl Effect After Treg Infusion For Gvhd Suppre...mentioning

confidence: 99%

“…On the other hand, mice receiving untouched PBMC showed improved survival rates than those in which Treg were depleted. Moreover, when untouched were used, GVL was decreased, but not abrogated ( 67 ). Overall, those studies point to an indispensable and nonredundant role for Treg in PTCy activity, which in turn does not disturb the GVL effect.…”

Section: Enhancing the Gvl Effect After Treg Infusion For Gvhd Suppre...mentioning

confidence: 99%

The impact of regulatory T cells on the graft-versus-leukemia effect

Pacini,

Soares,

Lacerda

2024

Front. Immunol.

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Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is the only curative therapy for many hematologic malignancies, whereby the Graft-versus-Leukemia (GVL) effect plays a pivotal role in controlling relapse. However, the success of GVL is hindered by Graft-versus-Host Disease (GVHD), where donor T cells attack healthy tissues in the recipient. The ability of natural regulatory T cells (Treg) to suppress immune responses has been exploited as a therapeutical option against GVHD. Still, it is crucial to evaluate if the ability of Treg to suppress GVHD does not compromise the benefits of GVL. Initial studies in animal models suggest that Treg can attenuate GVHD while preserving GVL, but results vary according to tumor type. Human trials using Treg as GVHD prophylaxis or treatment show promising results, emphasizing the importance of infusion timing and Treg/Tcon ratios. In this review, we discuss strategies that can be used aiming to enhance GVL post-Treg infusion and the proposed mechanisms for the maintenance of the GVL effect upon the adoptive Treg transfer. In order to optimize the therapeutic outcomes of Treg administration in allo-HSCT, future efforts should focus on refining Treg sources for infusion and evaluating their specificity for antigens mediating GVHD while preserving GVL responses.

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Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells

Cited by 10 publications

References 62 publications

Post-Transplant Cyclophosphamide Combined with Brilliant Blue G Reduces Graft-versus-Host Disease without Compromising Graft-versus-Leukaemia Immunity in Humanised Mice

Post-Transplant Cyclophosphamide Combined with Brilliant Blue G Reduces Graft-versus-Host Disease without Compromising Graft-versus-Leukaemia Immunity in Humanised Mice

Graft‐versus‐leukaemia immunity is retained following treatment with post‐transplant cyclophosphamide alone or combined with tocilizumab in humanised mice

The impact of regulatory T cells on the graft-versus-leukemia effect

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