Novel approaches to GVHD
| Therapies . | Mechanisms of action . | Data . | Ongoing clinical trials . |
|---|---|---|---|
| Prevention | |||
| Tocilizumab | Human monoclonal antibody against IL-6R | Phase 2 study of tocilizumab + Tac + MTX: 14% grade 2-4 acute GVHD, 3% grades 3 and 4 acute GVHD at 100 d39 | NCT03434730 |
| Abatacept | Costimulation blockade of CD28:CD80/86 to inhibit T cells | 2 of 10 patients with grade 2-4 acute GVHD, no day 100 TRM40 | NCT01743131 |
| NCT02867800 | |||
| Tregs | Regulate self-tolerance, limit GVHD while maintaining GVL effect | Modified expanded umbilical cord blood–derived Tregs: grade 2-4 acute GVHD 9% at 100 d42 | NCT01660607 |
| NCT00602693 | |||
| NCT01818479 | |||
| NCT01795573 | |||
| T-cell depletion (CD34 selection and selective ex vivo T-cell depletion) | Depletion of alloreactive T cells and selective αβ T-cell depletion, with preservation of γδ T cells and NK cells | CD34+ selection: grade 2-4 acute GVHD 22.7%, chronic GVHD 6.8%29 | NCT02323867 |
| NCT02600208 | |||
| NCT03301168 | |||
| NCT03047746 | |||
| NCT02345850 | |||
| Statins | Inhibit proinflammatory Th-1 differentiation, induce Treg expansion, and downregulate APCs | Phase 2 study of statin to both donors and recipients with Tac + MTX—grade 2-4 3.3%; chronic GVHD 52.3%46 | NCT03066466 |
| Vorinostat | Histone deacetylase inhibitor decreases inflammatory cytokines, enhances Treg function, and reduces GVHD while preserving GVL | Phase 2 study of vorinostat + Tac + MTX: grade 2-4 acute GVHD 22%, grades 3 and 4 acute GVHD 8%; chronic GVHD 29%51 | NCT01790568 |
| JAK inhibitors (itacitinib, ruxolitinib) | Reduction of proinflammatory cytokines, T-cell activation and function, preserves Tregs, GVL effect | Preclinical studies and use in treatment setting | NCT03320642 |
| Manipulation of the microbiome | Association of loss of diversity with increased GVHD and TRM; mediate anti-inflammatory cytokines and Tregs | Pilot study of fecal microbiota transfer early posttransplant: 2 of 13 developed acute GI GVHD66 | NCT02763033 |
| NCT02641236 | |||
| NCT03102060 | |||
| NCT03529825 | |||
| Treatment | |||
| Sirolimus | Inhibition of mTOR impairs T-cell signaling | Retrospective study of sirolimus as primary therapy for acute GVHD: 50% achieved CR vs 59% (matched historical control using 1 mg/kg prednisone)67 | NCT02806947 |
| JAK inhibitors (ruxolitinib, itacitinib) | Reduction of proinflammatory cytokines, T-cell activation and function, preserves Tregs, GVL effect | Retrospective study of steroid refractory acute GVHD with ruxolitinib, ORR 81.5%, and CR 46.3%68 | NCT03139604 |
| Phase 1 study of itacitinib in acute GVHD, ORR 88.3% first line and 64.7% steroid-refractory GVHD69 | |||
| α-1 antitrypsin | Serine protease inhibitor that modulates immune and inflammatory function through cytokine profiles | Phase 1/2 study of 12 patients with steroid-refractory GVHD: ORR 8 of 12, CR 4 of 1270 | NCT01700036 |
| NCT02953122 | |||
| NCT03172455 | |||
| IL-22 | Acts on intestinal stem cells to strengthen epithelial barrier function; tissue repair | Preclinical murine models show reduced mortality and improved intestinal pathology from GVHD with in vivo IL-2271 | NCT02406651 |
| Monoclonal antibodies (natalizumab, vedolizumab) | Targeting α4-integrins on activated lymphocytes mediating adhesion and trafficking | Used in inflammatory bowel diseases; case series of 5 patients with grade 4 GI GVHD, with responses in all patients72 | NCT02176031 |
| NCT02133924 | |||
| NCT02993783 | |||
| Extracorporeal photopheresis | Induction of Tregs(?), unknown | Retrospective studies of steroid refractory acute GHVD, ORR of ∼60%73 | NCT02524847 |
| NCT02151539 | |||
| Mesenchymal stromal cells | Inhibition of B- and T-cell activation, APCs, NK cells and increase Tregs | Several early phase studies with ORR 60-75%74 | NCT00603330 |
| NCT02687646 | |||
| NCT02336230 | |||
| NCT02770430 | |||
| NCT02359929 | |||
| Fecal microbiota transplant | Association of loss of diversity with increased GVHD and TRM; mediate anti-inflammatory cytokines and Tregs | Case series of fecal microbiota transplant: 3 out of 4 patients with CR48 | NCT03359980 |
| NCT03214289 | |||
| NCT03148743 |
| Therapies . | Mechanisms of action . | Data . | Ongoing clinical trials . |
|---|---|---|---|
| Prevention | |||
| Tocilizumab | Human monoclonal antibody against IL-6R | Phase 2 study of tocilizumab + Tac + MTX: 14% grade 2-4 acute GVHD, 3% grades 3 and 4 acute GVHD at 100 d39 | NCT03434730 |
| Abatacept | Costimulation blockade of CD28:CD80/86 to inhibit T cells | 2 of 10 patients with grade 2-4 acute GVHD, no day 100 TRM40 | NCT01743131 |
| NCT02867800 | |||
| Tregs | Regulate self-tolerance, limit GVHD while maintaining GVL effect | Modified expanded umbilical cord blood–derived Tregs: grade 2-4 acute GVHD 9% at 100 d42 | NCT01660607 |
| NCT00602693 | |||
| NCT01818479 | |||
| NCT01795573 | |||
| T-cell depletion (CD34 selection and selective ex vivo T-cell depletion) | Depletion of alloreactive T cells and selective αβ T-cell depletion, with preservation of γδ T cells and NK cells | CD34+ selection: grade 2-4 acute GVHD 22.7%, chronic GVHD 6.8%29 | NCT02323867 |
| NCT02600208 | |||
| NCT03301168 | |||
| NCT03047746 | |||
| NCT02345850 | |||
| Statins | Inhibit proinflammatory Th-1 differentiation, induce Treg expansion, and downregulate APCs | Phase 2 study of statin to both donors and recipients with Tac + MTX—grade 2-4 3.3%; chronic GVHD 52.3%46 | NCT03066466 |
| Vorinostat | Histone deacetylase inhibitor decreases inflammatory cytokines, enhances Treg function, and reduces GVHD while preserving GVL | Phase 2 study of vorinostat + Tac + MTX: grade 2-4 acute GVHD 22%, grades 3 and 4 acute GVHD 8%; chronic GVHD 29%51 | NCT01790568 |
| JAK inhibitors (itacitinib, ruxolitinib) | Reduction of proinflammatory cytokines, T-cell activation and function, preserves Tregs, GVL effect | Preclinical studies and use in treatment setting | NCT03320642 |
| Manipulation of the microbiome | Association of loss of diversity with increased GVHD and TRM; mediate anti-inflammatory cytokines and Tregs | Pilot study of fecal microbiota transfer early posttransplant: 2 of 13 developed acute GI GVHD66 | NCT02763033 |
| NCT02641236 | |||
| NCT03102060 | |||
| NCT03529825 | |||
| Treatment | |||
| Sirolimus | Inhibition of mTOR impairs T-cell signaling | Retrospective study of sirolimus as primary therapy for acute GVHD: 50% achieved CR vs 59% (matched historical control using 1 mg/kg prednisone)67 | NCT02806947 |
| JAK inhibitors (ruxolitinib, itacitinib) | Reduction of proinflammatory cytokines, T-cell activation and function, preserves Tregs, GVL effect | Retrospective study of steroid refractory acute GVHD with ruxolitinib, ORR 81.5%, and CR 46.3%68 | NCT03139604 |
| Phase 1 study of itacitinib in acute GVHD, ORR 88.3% first line and 64.7% steroid-refractory GVHD69 | |||
| α-1 antitrypsin | Serine protease inhibitor that modulates immune and inflammatory function through cytokine profiles | Phase 1/2 study of 12 patients with steroid-refractory GVHD: ORR 8 of 12, CR 4 of 1270 | NCT01700036 |
| NCT02953122 | |||
| NCT03172455 | |||
| IL-22 | Acts on intestinal stem cells to strengthen epithelial barrier function; tissue repair | Preclinical murine models show reduced mortality and improved intestinal pathology from GVHD with in vivo IL-2271 | NCT02406651 |
| Monoclonal antibodies (natalizumab, vedolizumab) | Targeting α4-integrins on activated lymphocytes mediating adhesion and trafficking | Used in inflammatory bowel diseases; case series of 5 patients with grade 4 GI GVHD, with responses in all patients72 | NCT02176031 |
| NCT02133924 | |||
| NCT02993783 | |||
| Extracorporeal photopheresis | Induction of Tregs(?), unknown | Retrospective studies of steroid refractory acute GHVD, ORR of ∼60%73 | NCT02524847 |
| NCT02151539 | |||
| Mesenchymal stromal cells | Inhibition of B- and T-cell activation, APCs, NK cells and increase Tregs | Several early phase studies with ORR 60-75%74 | NCT00603330 |
| NCT02687646 | |||
| NCT02336230 | |||
| NCT02770430 | |||
| NCT02359929 | |||
| Fecal microbiota transplant | Association of loss of diversity with increased GVHD and TRM; mediate anti-inflammatory cytokines and Tregs | Case series of fecal microbiota transplant: 3 out of 4 patients with CR48 | NCT03359980 |
| NCT03214289 | |||
| NCT03148743 |
APC, antigen-presenting cell; CR, complete response; GI, gastrointestinal; GVL, graft-versus-leukemia; IL-6R, interleukin-6 receptor; JAK, janus kinase; mTOR, mammalian target of rapamycin complex; NK, natural killer; ORR, overall response rate.