GvHD Prophylaxis

GvHD prophylaxis: KRP203 plus post-transplant cyclophosphamide

Graft-versus-host disease (GvHD) remains a major cause of non-relapse mortality after allogeneic hematopoietic stem cell transplant (allo-HSCT). There are multiple agents under investigation for the prevention of GvHD, which the GvHD Hub recently summarized as part of our October educational theme.  The current European Society for Blood and Marrow Transplantation (EBMT) and European LeukemiaNet (ELN) guidelines recommend patients receiving allo-HSCT with standard-risk disease from a matched-related donor or matched-unrelated donor (MUD), with bone marrow (BM) or peripheral blood stem cells as the stem cell source, are treated with1,2:

  • A calcineurin inhibitor (CNI), commonly tacrolimus or cyclosporine A (CSP)
  • An antimetabolite such as methotrexate or mycophenolate mofetil (MMF) for patients requiring rapid engraftment
  • In MUD, anti-thymocyte globulin (ATG) is recommended

Post-transplant cyclophosphamide (PTCy) has been increasingly utilized following haploidentical (haplo-) or matched-allo-HSCT, but its efficacy is only comparable to other regimens when combined with a CNI and MMF.3

The long-term administration of CNIs is associated with an increased risk of infection and chronic kidney disease. Therefore, developing GvHD prophylactic regimens that do not use CNIs represents an unmet need. Emi Yokoyama and colleagues recently published a study in Bone Marrow Transplantation investigating the use of short-term KRP203 in combination with PTCy as a novel GvHD prophylaxis regimen in murine models.3 Background information on KRP203 is provided in Table 1 below.

Table 1. Summary of KRP2033

What is KRP203?

A selective agonist of sphingosine-1-phosphate (SIP) receptor (SIPR) 1 (SIPR1) belonging to a new class of immunosuppressants called SIPR modulators

Mechanism of action  

SIP interacts with five G-protein coupled receptors (SIPR1-5). SIP regulates the egress of lymphocytes from secondary lymphoid organs (SLOs) in mice. Therefore, SIPR modulators can mitigate immune responses by sequestering T cells in the SLOs and making them more susceptible to PTCy cell death. They also have pro-apoptotic effects in the SLOs, not solely dependent on this sequestration

Other SIPR modulators

FTY720 was the first-in-class SIPR modulator and is approved by United States Food & Drug Administration (FDA) for the treatment of multiple sclerosis.4 However, it has an affinity for SIPR 1, 3, 4, and 5 meaning significant adverse events (AEs) were observed, particularly vascular AEs since vascular endothelial cells express SIPR1 and SIPR3

Differences between FTY720 and KRP203

SIPR1 is the only SIPR expressed on T-lymphocytes. KRP203 acts specifically on SIPR1 and therefore may be more tolerable. However, SIPR1 is also expressed on vascular endothelial cells so there may still be a risk of significant AEs

Potential uses

Currently utilized CNIs negatively impact Treg reconstitution. Therefore, SIPR modulators may represent an alternative to CNIs

Study design3
  • Female mice:
    • Cell donors: B6 (H-2b, CD45.2)
    • Cell donors: B6-Ly5a (H-2b, CD45.1)
    • Transplant recipients: B6D2F1 (H-2b/d, CD45.2)
  • Transplant conditioning: B6D2F1 recipients received 13.5 Gy total body irradiation across two doses with a four-hour interval followed by intravenous injection of 5 × 106 bone cells and 10 × 106 splenocytes from major histocompatibility complex-haploidentical B6 or syngeneic B6D2F1 donors on Day 0
    • Syngeneic controls: B6 mice transplanted with grafts from congenic B6-Ly5a donors
    • KRP203: orally administered: 1mg/kg daily from Day 0
Results3

Contraction of donor T cells in lymph nodes and effect on GvHD

  • Aim: evaluate T cell expansion and rates of GvHD following transplant
  • Method: transplant protocol and dosing schedule as above
  • Results:
    • Donor T cell expansion after allo-HSCT was greater on Day +4 and +7 compared to syngeneic controls
    • Allo-HSCT-treated mice that received KRP203 versus controls:
      • Trend to enhanced donor T cell expansion on Day +4
      • Earlier contraction of a donor T cell pool with lower levels of plasma interferon (IFN)-γ on Day +7
        • Further analysis indicates KRP203 facilitates sequestration and apoptosis of donor T cells in the mesenteric lymph nodes after allo-HSCT
      • GvHD: KRP203 from Day 0 to +6 significantly reduced morbidity and mortality of GvHD

Graft-versus-leukemia (GvL) effect

  • Aim: use in vivo bioluminescent imaging after haploidentical HSCT to monitor the effect of KRP203 on GvL
  • Method:
    • B6D2F1 mice were transplanted with the following on Day 0:
      • TCD-BM cells: 4 x 106
      • Purified T cells from B6 donors: 2 x 106
      • P815-luc+ cells (mouse mastocytoma cell line): 5 x 104
    • Subsequently received KRP203 at 3mg/kg daily from Day 0 to +28
      • Controls received 50mg/kg CSP, orally
  • Results:
    • TCD-BM alone transplanted mice: died with proliferation of P815-luc+
    • TCD-BM + T cell transplanted mice:
      • Placebo: potent GvL effects but ultimately succumbed to severe GvHD without tumor growth
      • CSP: no GvHD related deaths
      • KRP203: significant overall survival benefit with no GvHD related deaths. However, GvL effect was only retained until Day +30 before mice started to succumb to leukemia regrowth
  • Conclusion: KRP203 treatment led to a strong anti-GvHD effect with preservation of GvL effects

Combination of KRP203 and PTCy

  • Aim: evaluate if short-term KRP203 plus PTCy can reduce GvHD
  • Method: PTCy and KRP203 were administered as below:
    • PTCy dose: 50mg/kg
      • Although 100mg/kg PTCy on Day +3 significantly reduced GvHD mortality compared to 50mg/kg, in the clinical setting PTCy alone is not sufficient to reduce GvHD so a dose of 50mg/kg was used to mimic the real-world experience
    • KRP203 was administered for different durations:
      • Short-term: Days 0 to +4
      • Long-term: Days 0 to +28
  • Results:
    • KRP203 short-term administration ameliorated GvHD in haplo-transplanted mice when used with PTCy
      • Haplo-transplanted controls: GvHD was severe (100% mortality by Day +30 post-transplant)
      • PTCy alone: reduced morbidity and mortality due to GvHD (60% survival beyond Day +40)
      • PTCy + KRP203: further reduced morbidity and mortality by GvHD (100% survival beyond Day +40)
      • Pathology results: by gut, liver, and skin at four-weeks post-transplant:
        • PTCy alone: reduced GvHD pathology scores in gut, liver, and skin
        • PTCy + KRP203: further reduced GvHD pathological scores in the gut
      • Plasma levels of TNF-α on Day +14: lower in mice treated with PTCy + KRP203 compared to allogeneic mice receiving PTCy alone
      • Donor T cell infiltration on Day +15: PTCy suppressed donor T cell infiltration into each organ which was further reduced with KRP203 in the colon and skin

Regulatory T cell (Treg) reconstitution

  • PTCy (50mg/kg on Day +3) enhanced reconstitution of donor CD4+FoxP3+ Tregs in the spleen on Day +21 compared to allogeneic controls and those treated with CSP
  • PTCy + KRP203: significantly increased Tregs in the spleen on Day +21 compared to PTCy alone

Summary

Short-term administration of KRP203, a novel CNI-free GvHD prophylactic agent which targets SIPR1, can be used in combination with PTCy leading to:

  • Reduced donor T cell infiltration and pathological GvHD scores in the gut
  • Enhanced Treg reconstitution in the spleen
  • Amelioration of GvHD and improved survival after allo-HSCT compared to PTCy alone
  • A slightly, but not entirely, impaired GvL effect
References
  1. Ruutu T. et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Trans. 2014 Feb; 49:168–173. DOI: 10.1038/bmt.2013.107
  2. Penack O. Prophylaxis and treatment of GvHD: EBMT-ELN working group recommendations for standardized practice; 2019 May 18. Oral presentation. 1st EBMT GVHD Summit, Warsaw, PL
  3. Yokoyama E. et al. Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis. Bone Marrow Trans. 2019 Nov 04. DOI: 10.1038/s41409-019-0733-8 [Epub ahead of print]
  4. Novartis announces FDA approval of Gilenya® as the first disease-modifying therapy for pediatric relapsing multiple sclerosis. https://www.novartis.com/news/media-releases/novartis-announces-fda-approval-gilenya-first-disease-modifying-therapy-pediatric-relapsing-multiple-sclerosis Published 2018 May 11. [Accessed 2019 Nov 29]
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