Novel therapeutic approaches to promote tissue regeneration and repair in GVHD
| Treatment area/drug . | Mechanism of action . | Current trials . | Comments . |
|---|---|---|---|
| Regenerative failure | |||
| Recombinant human IL-22-Fc | In the gut , it promotes survival of transit-amplifying cells and ISCs via a STAT3-dependent mechanism; in the thymus, it increases thymic epithelial cell proliferation and survival.107 | NCT02406651, NCT04539470 | IL-22-Fc is well tolerated in human volunteers,108 but there is a theoretical risk of exacerbating IL-22–mediated pathology at other sites.102,103 |
| Keratinocyte growth factor (KGF) | In the gut, it promotes epithelial proliferation109; in the thymus, it induces proliferation of thymic epithelial cells and secretion of cytokines involved in thymocyte maturation.64 | — | Original aGVHD prevention trial demonstrated no benefit.110 In a non-transplantation setting, KGF unexpectedly reduced thymopoiesis in patients with alemtuzumab-based lymphopenia.111 |
| Mesenchymal stromal cells (MSCs) | Reduces apoptosis and promotes re-epithelialization after radiation-induced gut injury112 and promotes ILC3 function.38 | NCT0060330, NCT01045382 | Efficacy and mechanism of action in GVHD remains unclear (reviewed in Voermans and Hazenberg113). Different sources of MSCs and different methods of manipulation are potential confounders. MSCs derived from iPSCs show potential efficacy in a phase 1 study.114 |
| Stromal injury | |||
| Inhibition of sex steroids | Promotes expansion of early lymphoid progenitors and their thymic import and induces thymic expression of DLL4, a Notch ligand required for thymic regeneration.64 | — | Luteinizing hormone-releasing hormone agonist (LHRH-A) goserelin promoted an increase in CD4+ T-cell repertoire and an increase in TREC numbers and function without exacerbating GVHD.115 |
| Recombinant human IL-7 | Required for phosphoinositide 3 kinase and JAK-STAT–dependent pro-survival pathways in thymus. Promotes thymocyte development and maturation and peripheral maintenance of conventional and γδ T cells and ILCs.65 | NCT00684008 | Peripheral expansion of memory T cells was observed in a phase 1 trial after allogeneic stem cell transplantation with no excess of GVHD116; similar effects were observed when it was used in the context of infection, septic shock, and idiopathic CD4 lymphopenia.65 |
| Artificial thymic niche and bone marrow scaffold | Thymic organoid is generated by repopulation of a scaffold with thymic stroma and bone marrow progenitors.117 Transplantation of a bone marrow scaffold coated with BMP-2 stroma and presenting DLL4 to recruit stroma and and facilitate T-lineage specification of hematopoietic progenitor cells.118 | — | Proof-of-concept for thymus transplantation was demonstrated for DiGeorge syndrome and FOXN1 deficiency in humans.119 Transplantation of thymic organoids and bone marrow scaffolds is developmental. |
| Fibrosis | |||
| Anti-CSF1R | Monoclonal anti-CSF1R blocks macrophage infiltration of lung and skin.119 | NCT03604692, NCT04710576 | Timing of intervention may be important because early administration of CSF1 ameliorates experimental aGVHD.120 |
| Pirfenidone | Broad effects include reduced lung infiltration by macrophages, reduced frequency of T follicular helper cells, inhibition of TGF-β signaling and STAT3 activation in cultured fibroblasts, and attenuation of hedgehog signaling.105 | NCT03315741, | In preclinical models of cGVHD, pirfenidone was effective in bronchiolitis obliterans but less effective in skin disease.94 It has been approved for treatment of idiopathic pulmonary fibrosis.105 |
| Nilotinib | Tyrosine kinase inhibitor that blocks activation via C-ABL, PDGFR-α/β, and TGF-β.105 | NCT01810718, NCT01155817 | The safety profile was shown to be adequate in a phase 1 trial; efficacy testing is in progress. |
| Belumosudil (KD025) | Rho-associated kinase 2 inhibitor inhibits IL-17, IL-21, and STAT3.121 | Phase 1/2 dose escalation study and a phase 2 randomized study showed responses in heavily pretreated patients, including in organs with fibrotic manifestations.122,123 | |
| Glasdegib and sonidegib | Hedgehog inhibitor blocks epithelial-to-mesenchymal transition and release of collagen from fibroblasts.105 | NCT04111497 | Inhibition of hedgehog co-receptor Smoothened was ameliorated in a preclinical model of cGVHD.124 Despite clinical responses in cGVHD, a trial of sonidegib was terminated early because of poor tolerance.125 |
| Treatment area/drug . | Mechanism of action . | Current trials . | Comments . |
|---|---|---|---|
| Regenerative failure | |||
| Recombinant human IL-22-Fc | In the gut , it promotes survival of transit-amplifying cells and ISCs via a STAT3-dependent mechanism; in the thymus, it increases thymic epithelial cell proliferation and survival.107 | NCT02406651, NCT04539470 | IL-22-Fc is well tolerated in human volunteers,108 but there is a theoretical risk of exacerbating IL-22–mediated pathology at other sites.102,103 |
| Keratinocyte growth factor (KGF) | In the gut, it promotes epithelial proliferation109; in the thymus, it induces proliferation of thymic epithelial cells and secretion of cytokines involved in thymocyte maturation.64 | — | Original aGVHD prevention trial demonstrated no benefit.110 In a non-transplantation setting, KGF unexpectedly reduced thymopoiesis in patients with alemtuzumab-based lymphopenia.111 |
| Mesenchymal stromal cells (MSCs) | Reduces apoptosis and promotes re-epithelialization after radiation-induced gut injury112 and promotes ILC3 function.38 | NCT0060330, NCT01045382 | Efficacy and mechanism of action in GVHD remains unclear (reviewed in Voermans and Hazenberg113). Different sources of MSCs and different methods of manipulation are potential confounders. MSCs derived from iPSCs show potential efficacy in a phase 1 study.114 |
| Stromal injury | |||
| Inhibition of sex steroids | Promotes expansion of early lymphoid progenitors and their thymic import and induces thymic expression of DLL4, a Notch ligand required for thymic regeneration.64 | — | Luteinizing hormone-releasing hormone agonist (LHRH-A) goserelin promoted an increase in CD4+ T-cell repertoire and an increase in TREC numbers and function without exacerbating GVHD.115 |
| Recombinant human IL-7 | Required for phosphoinositide 3 kinase and JAK-STAT–dependent pro-survival pathways in thymus. Promotes thymocyte development and maturation and peripheral maintenance of conventional and γδ T cells and ILCs.65 | NCT00684008 | Peripheral expansion of memory T cells was observed in a phase 1 trial after allogeneic stem cell transplantation with no excess of GVHD116; similar effects were observed when it was used in the context of infection, septic shock, and idiopathic CD4 lymphopenia.65 |
| Artificial thymic niche and bone marrow scaffold | Thymic organoid is generated by repopulation of a scaffold with thymic stroma and bone marrow progenitors.117 Transplantation of a bone marrow scaffold coated with BMP-2 stroma and presenting DLL4 to recruit stroma and and facilitate T-lineage specification of hematopoietic progenitor cells.118 | — | Proof-of-concept for thymus transplantation was demonstrated for DiGeorge syndrome and FOXN1 deficiency in humans.119 Transplantation of thymic organoids and bone marrow scaffolds is developmental. |
| Fibrosis | |||
| Anti-CSF1R | Monoclonal anti-CSF1R blocks macrophage infiltration of lung and skin.119 | NCT03604692, NCT04710576 | Timing of intervention may be important because early administration of CSF1 ameliorates experimental aGVHD.120 |
| Pirfenidone | Broad effects include reduced lung infiltration by macrophages, reduced frequency of T follicular helper cells, inhibition of TGF-β signaling and STAT3 activation in cultured fibroblasts, and attenuation of hedgehog signaling.105 | NCT03315741, | In preclinical models of cGVHD, pirfenidone was effective in bronchiolitis obliterans but less effective in skin disease.94 It has been approved for treatment of idiopathic pulmonary fibrosis.105 |
| Nilotinib | Tyrosine kinase inhibitor that blocks activation via C-ABL, PDGFR-α/β, and TGF-β.105 | NCT01810718, NCT01155817 | The safety profile was shown to be adequate in a phase 1 trial; efficacy testing is in progress. |
| Belumosudil (KD025) | Rho-associated kinase 2 inhibitor inhibits IL-17, IL-21, and STAT3.121 | Phase 1/2 dose escalation study and a phase 2 randomized study showed responses in heavily pretreated patients, including in organs with fibrotic manifestations.122,123 | |
| Glasdegib and sonidegib | Hedgehog inhibitor blocks epithelial-to-mesenchymal transition and release of collagen from fibroblasts.105 | NCT04111497 | Inhibition of hedgehog co-receptor Smoothened was ameliorated in a preclinical model of cGVHD.124 Despite clinical responses in cGVHD, a trial of sonidegib was terminated early because of poor tolerance.125 |
CSF1R, colony-stimulating factor 1 receptor; IL-22-Fc, recombinant interleukin 22-immunoglobulin G fusion protein; iPSC, induced pluripotent stem cell; TREC, T-cell receptor excision circle.