Emerging approaches for the prevention and treatment of aGVHD
| Treatment or pathway . | Potential mechanism(s) of action . | Level of evidence . | References . |
|---|---|---|---|
| Small molecules | |||
| PKC inhibitors, such as R524 (Rigel Pharmaceuticals), and sotrastaurin (Novartis) | Inhibition of PKCα/θ, proteins that maintain immunologic synapse between APC and effector T cell | Preclinical (mouse) Sotrastaurin being investigated in solid organ transplant clinical trials | 125,126 |
| Sphingosine 1-phosphate receptor agonist FTY720 (fingolimod; Gilenya Pharmaceuticals) | Modulates DC function and lymphocyte efflux from secondary lymphoid organs, enhancement of endothelial barrier function | Preclinical (mouse) | 127 |
| Hypomethylating agents azacitidine and decitabine | Induction of FOXP3 expression | Preclinical (mouse) phase 1/2 clinical | 128,129 |
| Retinoic acid signaling | Reduction of T-cell homing, reducing Th1 differentiation, inducing Tregs | Preclinical (mouse) | 130 |
| Tim-3/Gal-9 pathway | Increased activation-induced T-cell death in the absence of Tregs | Preclinical (mouse) | 131 |
| PDL-1 pathway | Coinhibitory molecule, conversion of Th1 cells to Tregs | Preclinical (mouse) | 132 |
| IDO | Rate-limiting enzyme in tryptophan (required for T-cell proliferation) metabolism | Preclinical (mouse, human) | 133,134 |
| Arginase-1 | L-arginine depletion, reducing T-cell signaling and inflammatory cytokines | Preclinical (mouse) | 59 |
| TLR/MyD88 signaling inhibitors | Interfere with danger signaling, especially via inhibitory oligonucleotides against TLR9, to reduce inflammation | Preclinical (mouse) | 135 |
| Notch/notch ligand inhibitors | Detal-like1/4 (notch ligand) inhibitor given peritransplant prevented GVHD, while Notch 1 inhibitor lead to intestinal toxicity | Preclinical (mouse) | 136 |
| Cytokine/growth factor modulation | |||
| JAK/STAT inhibition | Reduction in inflammatory cytokines | Preclinical, case report | 137,138 |
| IL-17 downregulation | Curcumin downregulates IFNγ and IL-17 production, ameliorating aGVHD | Preclinical (mouse) | 139 |
| IL-21 blockade | Enhances generation of inducible Tregs | Preclinical (mouse) | 140 |
| IL-22 augmentation | Protective factor for intestinal stem cells under immune attack | Preclinical (mouse) | 141 |
| IL-23 blockade | Reduces inflammatory cytokines, T-cell trafficking, gut protection | Preclinical (mouse) | 66,142 |
| Case report, phase 2 (ongoing) | |||
| Cell-based therapies | |||
| MSCs | Suppress immune effector functions, secrete cytokines/growth factors for tissue repair and angiogenesis, can be obtained from related donors or third party | Phase 3, not yet reported in peer-reviewed literature (NCT00366145) | 124,143 |
| MAPCs | No expression of classical HLA class I markers (distinct from MSC), suppress T-cell activation via prostaglandin E2 synthesis, but only if colocalized with T cells at sites of activation | Preclinical (mouse) | 144,145 |
| Tregs | Expanded from umbilical cord blood, reduced aGVHD grade II-IV incidence from 61% to 43% in double UCB HCT (historical control); in haploidentical-related donors, Tregs reduced GVHD and enhanced immune reconstitution | Phase 1 | 54,146 |
| TRAIL+ T cells | Cytolytic mechanism against both tumor cells and alloreactive T cells | Preclinical (mouse) | 147 |
| NKs | GVHD protection only conferred if infusion was derived from Ly49-mismatched donor | Preclinical (mouse) | 148 |
| NKTs | Invariant NKTs attenuated murine GVHD in association with increased IL-2, IL-4, and IL-5 levels | Preclinical (mouse) | 149 |
| DCs | Tolerogenic DCs enhanced immunosuppressive cytokines in circulation, increased Tregs | Preclinical (mouse) | 150 |
| MDSCs | L-arginine depletion, contact-dependent immunosuppression | Preclinical (mouse) | 59 |
| Microbiota | |||
| α-defensins | Antimicrobial peptides secreted by intestinal Paneth cells, a target of GVHD | Preclinical (mouse) | 151 |
| Physiologic diversity | GVHD causes increase in Lactobacillales and decreases in Clostridiales, resulting in loss of physiologic diversity in gut bacteria | Preclinical (mouse and human) | 152 |
| Candida colonization | Patients colonized with Candida spp. had an increased incidence of grade II-IV GVHD (50% vs 32%) | Preclinical (human) | 153 |
| α-galactosylceramide (RGI-2001; RegImmune) | Produced by microbiome, can bind C1d and activate NKTs, induce Tregs | Preclinical (mouse) | 154,155 |
| Phase 1/2a (ongoing) | |||
| Donor-based immunomodulation | |||
| KGF (palifermin) | Epithelial, including thymic cytoprotection, inflammatory cytokine response, skewing toward Th2 cytokine response, although there was no reduction in GVHD when recipients were treated with palifermin in a phase 1/2 clinical trial | Preclinical (mouse) | 156,157 |
| Statins | Retrospective study demonstrated reduced grade III-IV GVHD in related HCT from statin-treated donors | Preclinical (mouse, human) | 158 |
| Phase 2 (ongoing) |
| Treatment or pathway . | Potential mechanism(s) of action . | Level of evidence . | References . |
|---|---|---|---|
| Small molecules | |||
| PKC inhibitors, such as R524 (Rigel Pharmaceuticals), and sotrastaurin (Novartis) | Inhibition of PKCα/θ, proteins that maintain immunologic synapse between APC and effector T cell | Preclinical (mouse) Sotrastaurin being investigated in solid organ transplant clinical trials | 125,126 |
| Sphingosine 1-phosphate receptor agonist FTY720 (fingolimod; Gilenya Pharmaceuticals) | Modulates DC function and lymphocyte efflux from secondary lymphoid organs, enhancement of endothelial barrier function | Preclinical (mouse) | 127 |
| Hypomethylating agents azacitidine and decitabine | Induction of FOXP3 expression | Preclinical (mouse) phase 1/2 clinical | 128,129 |
| Retinoic acid signaling | Reduction of T-cell homing, reducing Th1 differentiation, inducing Tregs | Preclinical (mouse) | 130 |
| Tim-3/Gal-9 pathway | Increased activation-induced T-cell death in the absence of Tregs | Preclinical (mouse) | 131 |
| PDL-1 pathway | Coinhibitory molecule, conversion of Th1 cells to Tregs | Preclinical (mouse) | 132 |
| IDO | Rate-limiting enzyme in tryptophan (required for T-cell proliferation) metabolism | Preclinical (mouse, human) | 133,134 |
| Arginase-1 | L-arginine depletion, reducing T-cell signaling and inflammatory cytokines | Preclinical (mouse) | 59 |
| TLR/MyD88 signaling inhibitors | Interfere with danger signaling, especially via inhibitory oligonucleotides against TLR9, to reduce inflammation | Preclinical (mouse) | 135 |
| Notch/notch ligand inhibitors | Detal-like1/4 (notch ligand) inhibitor given peritransplant prevented GVHD, while Notch 1 inhibitor lead to intestinal toxicity | Preclinical (mouse) | 136 |
| Cytokine/growth factor modulation | |||
| JAK/STAT inhibition | Reduction in inflammatory cytokines | Preclinical, case report | 137,138 |
| IL-17 downregulation | Curcumin downregulates IFNγ and IL-17 production, ameliorating aGVHD | Preclinical (mouse) | 139 |
| IL-21 blockade | Enhances generation of inducible Tregs | Preclinical (mouse) | 140 |
| IL-22 augmentation | Protective factor for intestinal stem cells under immune attack | Preclinical (mouse) | 141 |
| IL-23 blockade | Reduces inflammatory cytokines, T-cell trafficking, gut protection | Preclinical (mouse) | 66,142 |
| Case report, phase 2 (ongoing) | |||
| Cell-based therapies | |||
| MSCs | Suppress immune effector functions, secrete cytokines/growth factors for tissue repair and angiogenesis, can be obtained from related donors or third party | Phase 3, not yet reported in peer-reviewed literature (NCT00366145) | 124,143 |
| MAPCs | No expression of classical HLA class I markers (distinct from MSC), suppress T-cell activation via prostaglandin E2 synthesis, but only if colocalized with T cells at sites of activation | Preclinical (mouse) | 144,145 |
| Tregs | Expanded from umbilical cord blood, reduced aGVHD grade II-IV incidence from 61% to 43% in double UCB HCT (historical control); in haploidentical-related donors, Tregs reduced GVHD and enhanced immune reconstitution | Phase 1 | 54,146 |
| TRAIL+ T cells | Cytolytic mechanism against both tumor cells and alloreactive T cells | Preclinical (mouse) | 147 |
| NKs | GVHD protection only conferred if infusion was derived from Ly49-mismatched donor | Preclinical (mouse) | 148 |
| NKTs | Invariant NKTs attenuated murine GVHD in association with increased IL-2, IL-4, and IL-5 levels | Preclinical (mouse) | 149 |
| DCs | Tolerogenic DCs enhanced immunosuppressive cytokines in circulation, increased Tregs | Preclinical (mouse) | 150 |
| MDSCs | L-arginine depletion, contact-dependent immunosuppression | Preclinical (mouse) | 59 |
| Microbiota | |||
| α-defensins | Antimicrobial peptides secreted by intestinal Paneth cells, a target of GVHD | Preclinical (mouse) | 151 |
| Physiologic diversity | GVHD causes increase in Lactobacillales and decreases in Clostridiales, resulting in loss of physiologic diversity in gut bacteria | Preclinical (mouse and human) | 152 |
| Candida colonization | Patients colonized with Candida spp. had an increased incidence of grade II-IV GVHD (50% vs 32%) | Preclinical (human) | 153 |
| α-galactosylceramide (RGI-2001; RegImmune) | Produced by microbiome, can bind C1d and activate NKTs, induce Tregs | Preclinical (mouse) | 154,155 |
| Phase 1/2a (ongoing) | |||
| Donor-based immunomodulation | |||
| KGF (palifermin) | Epithelial, including thymic cytoprotection, inflammatory cytokine response, skewing toward Th2 cytokine response, although there was no reduction in GVHD when recipients were treated with palifermin in a phase 1/2 clinical trial | Preclinical (mouse) | 156,157 |
| Statins | Retrospective study demonstrated reduced grade III-IV GVHD in related HCT from statin-treated donors | Preclinical (mouse, human) | 158 |
| Phase 2 (ongoing) |
IDO, indoleamine 2,3 dioxygenase; IFN, interferon; JAK, Janus kinase; KGF, keratinocyte growth factor; MAPC, multipotent adult stromal cell; PDL, programmed death ligand; PKC, protein kinase C; STAT, signal transducer and activator of transcription; TRAIL, TNF-related apoptosis inducing ligand; UCB, umbilical cord blood.