Table 1.
Developing strategies for aGVHD prevention.
| Teff depletion | Inhibition of signal 1 of Teff activation | Inhibition of signal 2 of Teff activation | Inhibition of signal 3 of Teff activation | Inhibition of Teff trafficking | Promotion of immune tolerance | Modulation of microenvironment | ||
|---|---|---|---|---|---|---|---|---|
| Developing strategies | Ongoing clinical trial | Main putative mechanisms of action | ||||||
|
Ex vivo depletion of TCRαβ+/CD19+ donor cells [phase I–II (147)] |
NCT04088760 (phase II) NCT02508038 (phase I) |
X | ||||||
|
Ex vivo depletion of CD45RA+ naive T cells [phase II (148)] |
X | |||||||
| Ex vivo photodepletion of anti-host reactive donor T cells (Kiadis) [phase II (149)] | NCT02999854 (phase III) | X | X | |||||
| Proteasome inhibitors (bortezomib) [phase I–II (146, 150, 151)] |
NCT03945591 (phase II) NCT03082677 (phase II) NCT01991301 (phase I) NCT02145403 (phase I–II) |
X | X | X | X | |||
|
α-CTLA-4 Ig (abatacept, belatacept) [phase II (152–156)] |
NCT02867800 (phase I) NCT01743131 (phase II) NCT04380740 (phase II) |
X | ||||||
| Anti-IL-6 receptor antibody (tocilizumab) [phase I–II (52, 53)] |
NCT03434730 (phase II) | X | X | |||||
| Janus kinases inhibitors (anti-JAK1/2 ruxolitinib, and baricitinib; anti-JAK1 itacitinib) |
NCT02806375 (phase I–II) NCT04131738 (phase I) NCT04127721 (phase II) NCT03755414 (phase I) NCT03320642 (phase I) |
X | X | X | ||||
| Demethylating agents (5-azacytidine, decitabine) [phase I–II (157)] |
NCT00813124 (phase II) NCT01758367 (phase I–II) |
X | X | X | X | X | X | X |
| Histone deacetylase inhibitors (vorinostat, panobinostat) [phase I–II (158, 159)] |
NCT03842696 (phase I–II) NCT03842696 (phase I–II) NCT02588339 (phase II) |
X | X | X | X | X | X | X |
| CCR5 blocker (maraviroc) [phase I–II (74, 146, 160)] |
NCT02799888 (phase II) | X | ||||||
|
α4β7 integrin blocker (vedolizumab) (phase I–II) (161) |
NCT03657160 (phase III) | X | ||||||
| Low dose IL-2 [phase I (162, 163)] |
NCT02659657 (phase II) | X | ||||||
| Treg infusion [phase I–II (reviewed in (164)] |
NCT01795573 (phase I) NCT03977103 (phase II) NCT04013685 (phase I) |
X | ||||||
| Mesenchymal stromal cells [phase I–II (reviewed in (165))] |
NCT02270307 (phase II–III) NCT01045382 (phase II) NCT04247945 (phase II–III) |
X | ||||||
| iNKT cells [αgalCer, phase II (166) , TLI conditioning (129)] |
NCT03605953 NCT00631072 |
X | ||||||
| Recombinant urate-oxidase [phase I (167)] |
– | X | ||||||
| Alpha-1-antitrypsin | NCT03805789 (phase II-III) | X | ||||||
| Keratinocyte growth factor [phase I-II (168, 169)] | – | X | ||||||
| Probiotics and fecal material transplantation [phase I-III (170–172)] |
NCT03720392 (phase II) | X | ||||||
| Prebiotics |
NCT02805075 (phase I) NCT02763033 (phase II) |
X | ||||||
Strategies Aimed at Limiting Alloreactivity of Donor Immune Cells (Mainly T Cells) Against Host Tissues (red); Strategies Aimed at Promoting Immune Tolerance (blue); Strategies Aimed at Modulating Target Tissue Environment (green).