Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression

Abstract

Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient’s condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.

Hematopoietic stem cell–derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide

“…These results may help elucidate the underlying immune mechanisms by which PTCy prevents chronic GVHD as well as acute GVHD. We previously reported that PTCy ameliorated acute GVHD in a dose-dependent manner and that 50 mg/kg PTCy alone was sufficient to prevent GVHD, whereas this dose of PTCy reduced graft-versus-leukemia (GVL) activity in the MHC-haploidentical BMT system ( 49 ). While a previous study evaluated GVL activity and acute GVHD, the current study primarily addressed clinical symptoms and immune abnormalities related to chronic GVHD and the impact of PTCy using fewer donor T cells in the same mouse BMT system.…”

CAR-NKT cell therapy: a new promising paradigm of cancer immunotherapy

“…The cytotoxicity and amount of cytokine reaction in NKT cells depend on factors such as glycolipid antigens, the subtype of NKT cells, and the tissue location of NKT cells [ 28 ]. The α-GalCer is a synthetic glycolipid discovered in a sponge, so-called Agelas mauritianus, that can bind to TCR and other receptors [ 29 ]. The α-galactosylceramide (α-GalCer) ligand activates the NKT cells by binding to CD1d receptors on antigen-presenting cells (APCs) [ 30 ].…”

Sphingolipid metabolism in T cell responses after allogeneic hematopoietic cell transplantation

“…A subset of patients treated with RGI-2000 exhibit an increase in the number of Ki-67 + Helios + Foxp3 + cells, suggesting that a-galactosyl ceramide can expand natural Tregs in allo-HCT patients (53). In a haploidentical HCT mouse model, administration with a reduced dose of cyclophosphamide (PTC) followed by agalactosyl ceramide induces an NKT2 rather than NKT1 phenotype and early recovery of CD4 + Foxp3 + Tregs, which prevents GVHD while maintaining GVL effects (54). However, administration of KRN7000, another a-galactosyl ceramide derivative promotes dendritic cell (DC)-dependent NK and c o n v e n t i o n a l T -c e l l a c t i v a t i o n a n d u n e x p e c t e d proinflammation cytokines IFN-g/TNF-a production that leads to hyperacute GVHD in multiple murine HCT models (55).…”