Calcineurin Inhibitors Inhibit Tolerance Induction By Suppressing Terminal Differentiation of Donor Exhausted T Cells after Allogeneic SCT

Senjo, Hajime; Hashimoto, Daigo; Kubota, Shinpei; Tanaka, Yuki; Harada, Shinpei; Yoneda, Kazuki; Zhang, Zixuan; Chen, Xuanzhong; Kikuchi, Ryô; Hasegawa, Yuta; Ohigashi, Hiroyuki; Ara, Takahide; Hasegawa, Yoshinori; Murakami, Masaaki; Teshima, Takanori

doi:10.1182/blood-2022-158842

Cited by 3 publications

(5 citation statements)

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“… 29 , 30 , 31 More recent work suggests that administration of Cy before CNI abrogates the CNI effect of inhibiting T-cell exhaustion, whereas administration of CNI before transplantation fails to prevent chronic GVHD. 32 Although these mechanisms remain incompletely elucidated, use of PTCY for GVHD prevention has undergone refinements in recent years. 33 Early reports on the use of PTCY in the peritransplant period emphasized that this regimen obviated the need for T-cell depletion, preserving the GVT effect that is critical to the success of nonmyeloablative (NMA) transplantation.…”

Section: Discussionmentioning

confidence: 99%

Posttransplant cyclophosphamide vs tacrolimus–based GVHD prophylaxis: lower incidence of relapse and chronic GVHD

Maurer

Inyang

et al. 2023

Blood Advances

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The ability of post-transplant cyclophosphamide (PTCY) to facilitate stem cell transplantation using HLA-haplotype-mismatched donors has spurred interest in whether PTCY can improve clinical outcomes in patients with HLA-matched unrelated donors undergoing peripheral blood stem cell transplantation (PBSCT). We investigated our institutional experience with 8/8 or 7/8 HLA-matched unrelated donor PBSCT using PTCY-based GVHD prophylaxis compared to conventional tacrolimus-based regimens. We compared overall survival (OS), progression-free survival (PFS), relapse, non-relapse mortality, and acute and chronic GVHD in 107 adult patients receiving a PTCY-based regimen versus 463 patients receiving tacrolimus-based regimens for GVHD prophylaxis. All patients were transplanted for hematologic malignancies. The two cohorts were well balanced for baseline characteristics except that more patients in the PTCY cohort received 7/8 matched PBSCT. There was no difference in acute GVHD. All-grade chronic GVHD and moderate-severe chronic GVHD were substantially reduced in patients receiving PTCY compared to tacrolimus-based regimens (2-year moderate-severe chronic GVHD: 12% vs 36%, p<0.0001). Recipients of PTCY-based regimens also had a lower incidence of relapse compared to recipients of tacrolimus-based regimens (25% vs. 34% at 2-years, p=0.027), primarily in patients who received reduced intensity conditioning. This led to improved PFS in the PTCY cohort (64% vs 54% at 2 years, p=0.02). In multivariable analysis, hazard ratio was 0.59 (p=0.015) for PFS and subdistribution hazard ratio was 0.27 (p<0.0001) for moderate-severe chronic GVHD and 0.59 (p=0.015) for relapse. Our results suggest that PTCY prophylaxis is associated with lower rates of relapse and chronic GVHD in patients who receive HLA-matched unrelated donor PBSCT.

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Section: Discussionmentioning

confidence: 99%

Posttransplant cyclophosphamide vs tacrolimus–based GVHD prophylaxis: lower incidence of relapse and chronic GVHD

Maurer

Inyang

et al. 2023

Blood Advances

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“…Unexpectedly, RIP1 kinase inhibition also resulted in marked increases in T regs in GVHD target organs and the restoration of immunologic homeostasis. T cell exhaustion during GVHD has been well described ( 47 , 48 ), and GNE684 treatment reduced the expression of two T cell exhaustion markers and improved T cell functional responses to third-party alloantigens. We hypothesize that the effect of RIP1 kinase inhibition on T regs is indirect, and it is known that the reversal of dysbiosis can reduce GVHD and induce the expansion of T regs ( 49 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RIP1 improves immune reconstitution and reduces GVHD mortality while preserving graft-versus-leukemia effects

Prado-Acosta,

Jeong,

Utrero-Rico

et al. 2023

Sci. Transl. Med.

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Graft-versus-host disease (GVHD) remains the major cause of morbidity and nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT). Inflammatory cytokines mediate damage to key GVHD targets such as intestinal stem cells (ISCs) and also activate receptor interacting protein kinase 1 (RIP1; RIPK1), a critical regulator of apoptosis and necroptosis. We therefore investigated the role of RIP1 in acute GVHD using samples from HCT patients, modeling GVHD damage in vitro with both human and mouse gastrointestinal (GI) organoids, and blocking RIP1 activation in vivo using several well-characterized mouse HCT models. Increased phospho-RIP1 expression in GI biopsies from patients with acute GVHD correlated with tissue damage and predicted NRM. Both the genetic inactivation of RIP1 and the RIP1 inhibitor GNE684 prevented GVHD-induced apoptosis of ISCs in vivo and in vitro. Daily administration of GNE684 for 14 days reduced inflammatory infiltrates in three GVHD target organs (intestine, liver, and spleen) in mice. Unexpectedly, GNE684 administration also reversed the marked loss of regulatory T cells in the intestines and liver during GVHD and reduced splenic T cell exhaustion, thus improving immune reconstitution. Pharmacological and genetic inhibition of RIP1 improved long-term survival without compromising the graft-versus-leukemia (GVL) effect in lymphocytic and myeloid leukemia mouse models. Thus, RIP1inhibition may represent a nonimmunosuppressive treatment for GVHD.

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“…Although widespread adoption of prophylaxis with calcineurin inhibitors (CNIs) has improved the rates of acute graft-versus-host-disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HCT), the incidence of chronic GVHD (cGVHD) is rising. 1,2 cGVHD has significant impacts on long-term quality of life and is a primary cause of late morbidity and mortality after allo-HCT. The pathophysiology is complex, involving dysregulation of immune effector populations and disruption of central and peripheral tolerance pathways.…”

Section: Calcineurin Inhibitor Inhibits Tolerance Induction By Suppre...mentioning

confidence: 99%

“…Senjo et al 1 leverage a mouse model of HCT to explore how CNIs may affect tolerance and development of cGVHD. The authors demonstrated that donor T cells rapidly differentiate into terminally exhausted T cells (Tex) after HCT in the absence of CNI, in part because of upregulation of TOX (thymocyte selection-associated HMG BOX), a master regulator of T-cell exhaustion.…”

Section: Calcineurin Inhibitor Inhibits Tolerance Induction By Suppre...mentioning

confidence: 99%

“…Through a series of refined mouse models, Senjo et al 1 provide novel insights into the role of CNI on the exhaustion pathway of donor T cells after allo-HCT, identifying a novel CNI-induced transitory Tex population, which could serve as a future therapeutic target. These results highlight the possible relevance of the timing of CNI initiation posttransplant, serving as a reminder of the importance of understanding the influence of immunosuppressive agents on posttransplant immunity.…”

Section: Calcineurin Inhibitor Inhibits Tolerance Induction By Suppre...mentioning

confidence: 99%

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Transplantation

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Calcineurin Inhibitors Inhibit Tolerance Induction By Suppressing Terminal Differentiation of Donor Exhausted T Cells after Allogeneic SCT

Cited by 3 publications

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Posttransplant cyclophosphamide vs tacrolimus–based GVHD prophylaxis: lower incidence of relapse and chronic GVHD

Posttransplant cyclophosphamide vs tacrolimus–based GVHD prophylaxis: lower incidence of relapse and chronic GVHD

Inhibition of RIP1 improves immune reconstitution and reduces GVHD mortality while preserving graft-versus-leukemia effects

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