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Translational and clinical advances in aGvHD
Table 1. Prophylactic strategies for acute graft-versus-host-disease.
Prophylaxis strategy
In vivo T-cell depletion/modulation
Ex vivo T-cell depletion
Regulatory T-cell enhancement
Cytokine targeting
Targeting T-cell co-stimulatory pathways
Intervention
Calcineurin inhibitors (tacrolimus, cyclosporine)
ATG
PTCy
Sirolimus (mTOR inhibitor)
Pan T-cell depletion a/β T-cell depletion
CD45RA (naïve) T-cell depletion
CD6 depletion Itolizumab
Treg:Tcon add back strategies Tregs
iNKT cells
Tociluzumab
CD28/CTLA-4 targeting (abatacept)
Level of evidence
Phase III RCT
Phase III RCT
Phase II/III RCT Phase II/III RCT
Phase II/III RCT Phase II single arm
First-in-human phase I/II
Phase II single arm Ongoing phase I/II
First-in-human phase I/II Phase I
Phase I/II
Phase III RCT Phase II RCT
Comments
Tac vs. CyA, less aGvHD with Tac but no survival advantage.
Either no reduction in aGvHD or reduction in aGvHD with significant
increase in NRM.
Lower rates of severe aGvHD but not grades II-IV aGvHD compared to CNI.
Lower rates of grades III-IV aGvHD in MAC and grades II-IV aGvHD in
RIC HSCT but no survival advantage.
Lower rates of grades III-IV aGvHD but no survival advantage. Graft failure sometimes an issue.
Promising GRFS of 70% in pediatric acute leukemia. Adult studies ongoing.
High aGvHD rates of 66% and hence investigational only for the moment.
aGvHD rates of 18%; monoclonal antibody (itolizumab) with FDA fast-track status now being tested.
Operationally complex and for the moment difficult to generalize.
Preliminary safety results encouraging; concerns about stability of ex vivo Treg explansion.
TLI-ATG regimen via iNKT cells with reported GvHD in only 2 of 37 recipients.
REGIMMUNE/sirolimus combination promising.
Tocilizumab vs. placebo; no improvement in aGvHD of any grade. CTLA-4 Ig (abatacept)+SOC compared to SOC in 8/8 and
7/8 HLA-matched HSCT with lower rates of grades III-IV aGvHD outcomes
and OS leading to FDA breakthrough designation.
aGvD: acute graft-versus-host disease; HSCT: hematopoietic stem cell transplantation; PTCy: post-transplant cyclophosphamide; ATG: anti-thymocyte globulin; RCT: randomized controlled trial; iNKT: invariant natural killer T cells; OS: overall survival; SOC: standard of care; FDA: US Food and Drug Administration; NRM: non-relapse mortality; aGvHD: acute graft-versus-host dis- ease; GRFS: GvHD free, relapse-free survival; CNI: calcineurin inhibitor.
tinib when added to steroids (vs. steroids alone) for upfront therapy of aGvHD in the closed GRAVITAS 301 trial (clin- icaltrials.gov NCT03139604) is notable. JAK-1 inhibition is capable of selectively suppressing Th1 and Th17 Teff cell subsets, with preserved activation of anti-inflammatory Treg cells dependent on the JAK2/JAK3 pathway; howev- er, the drug failed clinical efficacy, highlighting limitations in clinical trial design, optimal therapeutic target identifica- tion, or both. Data on the efficacy of selective JAK2 inhibitors in aGvHD are eagerly awaited, but it is possible that combination JAK1/2 blockade may be required for appropriate suppression of activation in Teff cells.
Although a number of cytokine-directed therapies previ- ously failed in the therapy of aGvHD (denileukin diftitox, tocilizumab, anti TNF-a), the efficacy of Rux is a milestone in the field, and a testament to the critical role of a ‘cytokine storm’ in aGvHD.
Alpha-1-antitrypsin - alpha-1-antitrypsin (AAT) is a serine protease inhibitor produced by the liver which has myriad functions including inhibition of proinflammatory plasma cytokines and induction of anti-inflammatory IL10, and in vivo induction of Treg. In preclinical aGvHD models, AAT reduced inflammatory cytokines, altered the ratio of Teff and Tregs and reduced levels of DAMP.92 In a phase I/II open label single center study in SR aGvHD patients (n=12), responses were seen in 8 of 12 patients with no sig- nificant toxicity.93 In a larger phase II multicenter study (n=40), ORR at D28 was 65% (CR 35%).94 Upfront AAT is being evaluated in a Blood and Marrow Transplant Clinical
Trials Network (BMT-CTN) phase III RCT evaluating cor- ticosteroids ± AAT (clinicaltrials.gov NCT04167514) as a promising non-toxic agent for high-risk aGvHD.
Targeting lymphocyte trafficking
Vedolizumab - lymphocyte trafficking to GvHD target organs is a key event leading to aGvHD. In the lower GI tract, Peyer’s patches (PP) and gut-associated lymphoid tis- sue (GALT) are the targets for alloreactive CD8+ T cells. Gut- tropic CD8+ cells express high levels of integrin β7 (a4β7) that binds its ligand mucosal addressin cell adhesion mole- cule 1 (MAdCAM 1) in the PP and GALT. Vedolizumab, a humanized mAb, targets a4β7 integrins and prevents Teff trafficking to the gut. A small proof of concept study (n=6) demonstrated responses in all patients with SR lower GI GvHD. In an international, retrospective review to evaluate the off-label use of vedolizumab (n=29), ORR was 64% and OS at 6 months was 54%.95 CMV reactivation and Clostridium difficile colitis were noted. Natalizumab, a selec- tive a4 subunit adhesion molecule inhibitor was studied in a phase II study with a response rate of approximately 30%.96 Vedolizumab is being studied in larger prophylactic (clinicaltrials.gov NCT03657160) and therapeutic (clinicaltrials.gov NCT02993783) trials for aGvHD.
Targeting immunologic tolerance
Extracorporeal photochemotherapy - extracorporeal pho- tochemotherapy (ECP) has been used for cGvHD for decades, and more recently for aGvHD with some suc-
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