Translation of immunosuppressive strategies from animal models of GVHD into clinical trials
| Main conclusion from the preclinical model of GVHD (y) . | Reference . | Main conclusion from the clinical trials (y) . | Reference . |
|---|---|---|---|
| CyA and MTX reduce GVHD in the canine GVHD model (1982) | 11 | MTX and CyA is superior to CyA alone for GVHD prophylaxis (1986). Phase 3 prospective, randomized trial | 12 |
| ATG prevents GVHD in DLA haplotype mismatched littermate dogs (1979) | 14 | Different types of ATG reduce the risk of acute and cGVHD in patients (1979, 2009, 2016). Phase 3 prospective, randomized trials (2009, 2016) | 15,16,127 |
| Corticosteroids reduce GVHD severity in mice (1990, 1995) | 20,21 | Corticosteroids are effective as first-line therapy for aGVHD in patients (1998, 2009). Phase 3 multicenter randomized trial (1998); retrospective analysis (2009) | 18,19 |
| IL-11 downregulated IL-12, and reduced aGVHD-related mortality (1998, 1999) | 22,23 | IL-11 leads to increased mortality in patients (2002). Phase 1/2 double-blind, placebo-controlled study | 29 |
| IL-1 blockade reduces GVHD in mice in some but not all models (1991) | 24 | IL-1 antagonist is not effective in the GVHD prophylaxis setting (2002). Phase 3 prospective placebo-controlled study | 36 |
| TNF-α antagonism reduces GVHD (1999, 2003) | 25,26 | Infliximab and corticosteroids are effective as initial treatment of GVHD. Prospective phase 3 study (2009); retrospective analysis (2011) | 44,128 |
| IL-6 blockade reduces aGVHD in mice (2009, 2011) | 27,28 | Early IL-6 inhibition with tocilizumab leads to a low risk of aGVHD (2014). Phase 1/2 single institution trial | 47 |
| Anti-CCR5 antibody treatment protects against aGVHD-related mortality (1999, 2003) | 48,49 | CCR5 inhibition prevents aGVHD of liver and gut before day 100 (2012). Phase 1/2 single institution trial | 129 |
| The sphingosine 1-phosphate receptor agonist FTY720 reduces GVHD (2003, 2007) | 53,54 | Active clinical study on KRP203 in patients undergoing allo-HCT (2016). Randomized, open-label phase 1/2 study | 57 |
| CTLA4-Ig reduces lethal murine GVHD (1994) | 58 | CD28:CD80/86 co-stimulation blockade with abatacept leads to low GVHD rates (2013). Single-arm feasibility study | 59 |
| KGF reduces but does not uniformly eliminate GVHD lethality in mice (1998, 1999) | 63,64 | Palifermin does not reduce aGVHD severity (2012) but there is a need for parenteral nutrition after TBI (2013). Radomized, double-blind, placebo-controlled trial (2012); retrospective analysis (2013) | 65,66 |
| Memory CD4+ T cells cause less aGVHD and cGVHD (2003, 2007, 2009) | 68,69,113 | Naive T-cell–depleted stem cell graft transfer is connected to less cGVHD and no change aGVHD incidence though more steroid responsiveness (2015). Single-arm, 2 site clinical trial | 70 |
| Photoinactivation of T-cell function with psoralen and UV radiation suppresses GVHD in mice (1991) | 71 | ECP is an effective therapy for aGVHD (2000, 2015). Pilot study (2000); meta-analysis of prospective studies for ECP (2015) | 72,73 |
| Statins reduce GVHD severity (2007, 2009) | 75,76 | Statin intake is connected to reduced GVHD incidence in patients (2010, 2010, 2013). Retrospective analysis (2010); prospective phase 2 trial, donor and recipient treatment (2013) | 77,-79 |
| HDAC inhibition reduced GVHD severity in mice (2008) | 81 | Vorinostat in combination with standard GVHD prophylaxis is associated with a low incidence of severe aGVHD (2014). | 82 |
| Phase 1/2 trial | |||
| JAK1/2 inhibition reduces aGVHD (2014, 2015) | 83,84 | JAK1/2 inhibition reduces aGVHD in patients refractory to multiple therapies (2015). Retrospective analysis | 85 |
| Proteasome inhibition with bortezomib reduces GVHD (2004) | 87 | Short-course, bortezomib-based GVHD prophylaxis yields low aGVHD rates (2009, 2012). Phase 1 trial (2009); prospective phase 1/2 trial (2012) | 88,89 |
| α-GalCer reduces GVHD (2005) | 92 | RGI-2001 is tested for GVHD prevention (2016). Phase 1/2 trial | 51 |
| CP can induce tolerance toward skin allografts (1989)93 and posttransplant CP reduced GVHD severity in mice (2014)95 | 93,95 | Posttransplantation CP is effective as single-agent aGVHD prophylaxis (2014). Open label multi-institutional trial | 97,98 |
| Main conclusion from the preclinical model of GVHD (y) . | Reference . | Main conclusion from the clinical trials (y) . | Reference . |
|---|---|---|---|
| CyA and MTX reduce GVHD in the canine GVHD model (1982) | 11 | MTX and CyA is superior to CyA alone for GVHD prophylaxis (1986). Phase 3 prospective, randomized trial | 12 |
| ATG prevents GVHD in DLA haplotype mismatched littermate dogs (1979) | 14 | Different types of ATG reduce the risk of acute and cGVHD in patients (1979, 2009, 2016). Phase 3 prospective, randomized trials (2009, 2016) | 15,16,127 |
| Corticosteroids reduce GVHD severity in mice (1990, 1995) | 20,21 | Corticosteroids are effective as first-line therapy for aGVHD in patients (1998, 2009). Phase 3 multicenter randomized trial (1998); retrospective analysis (2009) | 18,19 |
| IL-11 downregulated IL-12, and reduced aGVHD-related mortality (1998, 1999) | 22,23 | IL-11 leads to increased mortality in patients (2002). Phase 1/2 double-blind, placebo-controlled study | 29 |
| IL-1 blockade reduces GVHD in mice in some but not all models (1991) | 24 | IL-1 antagonist is not effective in the GVHD prophylaxis setting (2002). Phase 3 prospective placebo-controlled study | 36 |
| TNF-α antagonism reduces GVHD (1999, 2003) | 25,26 | Infliximab and corticosteroids are effective as initial treatment of GVHD. Prospective phase 3 study (2009); retrospective analysis (2011) | 44,128 |
| IL-6 blockade reduces aGVHD in mice (2009, 2011) | 27,28 | Early IL-6 inhibition with tocilizumab leads to a low risk of aGVHD (2014). Phase 1/2 single institution trial | 47 |
| Anti-CCR5 antibody treatment protects against aGVHD-related mortality (1999, 2003) | 48,49 | CCR5 inhibition prevents aGVHD of liver and gut before day 100 (2012). Phase 1/2 single institution trial | 129 |
| The sphingosine 1-phosphate receptor agonist FTY720 reduces GVHD (2003, 2007) | 53,54 | Active clinical study on KRP203 in patients undergoing allo-HCT (2016). Randomized, open-label phase 1/2 study | 57 |
| CTLA4-Ig reduces lethal murine GVHD (1994) | 58 | CD28:CD80/86 co-stimulation blockade with abatacept leads to low GVHD rates (2013). Single-arm feasibility study | 59 |
| KGF reduces but does not uniformly eliminate GVHD lethality in mice (1998, 1999) | 63,64 | Palifermin does not reduce aGVHD severity (2012) but there is a need for parenteral nutrition after TBI (2013). Radomized, double-blind, placebo-controlled trial (2012); retrospective analysis (2013) | 65,66 |
| Memory CD4+ T cells cause less aGVHD and cGVHD (2003, 2007, 2009) | 68,69,113 | Naive T-cell–depleted stem cell graft transfer is connected to less cGVHD and no change aGVHD incidence though more steroid responsiveness (2015). Single-arm, 2 site clinical trial | 70 |
| Photoinactivation of T-cell function with psoralen and UV radiation suppresses GVHD in mice (1991) | 71 | ECP is an effective therapy for aGVHD (2000, 2015). Pilot study (2000); meta-analysis of prospective studies for ECP (2015) | 72,73 |
| Statins reduce GVHD severity (2007, 2009) | 75,76 | Statin intake is connected to reduced GVHD incidence in patients (2010, 2010, 2013). Retrospective analysis (2010); prospective phase 2 trial, donor and recipient treatment (2013) | 77,-79 |
| HDAC inhibition reduced GVHD severity in mice (2008) | 81 | Vorinostat in combination with standard GVHD prophylaxis is associated with a low incidence of severe aGVHD (2014). | 82 |
| Phase 1/2 trial | |||
| JAK1/2 inhibition reduces aGVHD (2014, 2015) | 83,84 | JAK1/2 inhibition reduces aGVHD in patients refractory to multiple therapies (2015). Retrospective analysis | 85 |
| Proteasome inhibition with bortezomib reduces GVHD (2004) | 87 | Short-course, bortezomib-based GVHD prophylaxis yields low aGVHD rates (2009, 2012). Phase 1 trial (2009); prospective phase 1/2 trial (2012) | 88,89 |
| α-GalCer reduces GVHD (2005) | 92 | RGI-2001 is tested for GVHD prevention (2016). Phase 1/2 trial | 51 |
| CP can induce tolerance toward skin allografts (1989)93 and posttransplant CP reduced GVHD severity in mice (2014)95 | 93,95 | Posttransplantation CP is effective as single-agent aGVHD prophylaxis (2014). Open label multi-institutional trial | 97,98 |
CP, cyclophosphamide; DLA, dog leukocyte antigen.