In vivo stimulation of natural killer T cells and downstream regulatory T cells to reduce acute graft-versus-host disease

Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for many malignant and non-malignant hematological conditions but is limited by the development of acute and chronic graft-versus-host disease (GVHD) (1), which can have long-term impacts on survivorship (2).The addition of post-transplant cyclophosphamide with standard GVHD prophylaxis is increasingly being used in human leukocyte antigen (HLA)-matched HCT recipients receiving reduced intensity conditioning (3).In contrast, improvements in GVHD prophylaxis in HLA-matched HCT recipients requiring myeloablative conditioning remain to be developed.In a new clinical study, DeFilipp, Chen and colleagues used RGI-2001 with standard GVHD prophylaxis to demonstrate its safety and determine its efficacy in reducing acute GVHD in HLA-matched myeloablative HCT patients (4).This provides a potentially improved form of GVHD prophylaxis in this transplant setting.RGI-2001 is a liposomal formation of KRN7000, a synthetic derivative of α-galactosylceramide, which can bind CD1d (5) on antigen presenting cells to activate invariant natural killer T (iNKT) cells ( 6).This activation of iNKT cells can lead to the interleukin-4 (IL-4)-dependent proliferation of regulatory T cells (Tregs) (7).In pre-clinical studies, the iNKT cell-mediated expansion of Tregs can mitigate GVHD (7,8), while increased proportions of these cells can be associated with reduced GVHD (9).Notably, both KRN7000 (10) and RGI-2001 (11) can reduce GVHD in pre-clinical studies, with this effect by the latter due to the iNKT cell-mediated expansion of Tregs (11,12).Thus, RGI-2001 affords a potential additional therapy to activate and increase iNKT cells and Tregs to prevent in GVHD in allogeneic HCT recipients.Following on from an earlier phase 2a trial, in which a single dose of RGI-2001 (1 or 100 μg/kg) administered on the day of allogeneic HCT was deemed to be safe and to potentially reduce GVHD ( 13), DeFilipp et al. (4) conducted an open-label, single-arm multicenter phase 2b trial with RGI-2001 in 49 blood cancer patients (n=27, 55.1% acute myeloid leukemia) receiving hematopoietic cells (n=40, 81.6% from peripheral blood) from HLA-matched (8/8 alleles) related (n=16, 32.7%) or unrelated (n=32, 65.3%)