Editorial theme | Using a stem cell source as prophylaxis for cGvHD

Peripheral blood stem cells (PBSC) have become the predominant source of cells for hematopoietic stem cell transplantation (HSCT) because of ease of collection and faster recovery of donors, and improvements in engraftment in patients who undergo related or unrelated donor allogeneic HSCT (allo-HSCT).¹

However, the stem cell source plays an important role in the development of graft-versus-host disease (GvHD). Studies evaluating the incidence of chronic GvHD (cGvHD) after PBSC versus bone marrow (BM) transplantation from HLA-matched related or unrelated donor demonstrate a higher incidence of cGvHD with PBSC as the stem cell source.¹

Also, a study comparing the outcomes of transplanted patients with Hodgkin and non-Hodgkin lymphoma showed that the 2-year severe cGvHD was higher with umbilical cord blood (UCB)  and haploidentical (haplo-)PB versus haplo-BM.

Furthermore, Rohtesh S. Mehta et al., reported that BM grafts from matched sibling donors achieve better results in terms of GvHD-free, relapse-free survival (GRFS) when compared with PB grafts from any donor or to UCB.²

The advantage of BM as stem cell source was confirmed in a recent study where patients with a haploidentical BM donor had better GRFS compared with those with a one-antigen mismatched unrelated donor using either a BM or PB graft, or those receiving a UCB graft after reduced-intensity conditioning (RIC).

A strategy that has recently emerged is the use of ex vivo expanded UCB stem cells. Omidubicel is a cryopreserved allogeneic stem cell-based product which combines ex vivo expanded UCB-derived CD34-positive progenitor cells and non-expanded myeloid and lymphoid cells, which allows for faster hematopoietic recovery compared with patients receiving standard UCB, but no improvement has been noted in the incidence of acute GvHD (aGvHD) or cGvHD when compared with standard UCB.

Cell-based strategies to reduce cGvHD

CD34+ cell selection and expansion

The higher incidence of cGvHD observed after PBSC and UCB transplantation is primarily due to the presence of a higher number of T cells compared to BM grafts. Thus, a possible strategy to reduce cGvHD risk is represented by T-cell depletion of PBSC. T-cell depletion via selection of CD34+ cells has demonstrated promising results with lower incidence of cGvHD and overall survival and relapse-free survival probabilities comparable to those observed with unmodified PBSCT.¹

A novel way of expanding CD34+ cells is demonstrated with MGTA-456, a first-in-class cell therapy utilizing an aryl hydrocarbon receptor antagonist for expansion of CD34+ CD90+ cells in vitro. During the 2021 Transplantation and Cellular Therapy Meetings of ASTCT and CIBMTR, Heather E. Stefanski reported results from a study (NCT03674411) evaluating the safety and efficacy of cryopreserved MGTA-456 in patients with high-risk malignancy. The expansion of CD34+ CD90+ cells in MGTA-456 resulted in faster hematopoietic recovery, complete engraftment, and improved HLA match. Also, fewer patients had Grade II─IV aGvHD (24% in the MGTA-456 arm vs 46% in the control arm; p = 0.04) while no significant differences were observed in the incidence of Grade III─IV aGvHD and cGvHD.³

Another study, presented during the 2021 Transplantation and Cellular Therapy Meetings of ASTCT and CIBMTR, investigated stem cells mobilization with MGTA-145 (a CXCR2 agonist) in combination with plerixafor (a CXCR4 inhibitor) in a phase I clinical study. Results, reported by Kevin A. Goncalves, showed rapid and robust stem cells mobilization with MGTA-145 plus plerixafor. In addition, MGTA-145 plus plerixafor grafts resulted in significantly less GvHD compared to granulocyte-colony stimulating factor (G-CSF) or plerixafor grafts in a xenograft mouse model.⁴

T-cell depletion

An alternative approach to in vivo alloreactive T-cell depletion is represented by the use of posttransplant cyclophosphamide (PTCy). The use of PTCy after haploidentical transplants or after matched related and matched unrelated allo-HSCT has shown promising results in terms of GvHD incidence and GRFS.

Two retrospective studies evaluated the impact of donor type on the outcome of patients with acute leukemia who underwent allo-HSCT using PTCy for GvHD prophylaxis. Results from these studies showed that the use of PTCy in patients who received allo-HSCT from haplo donors led to a reduction in the risk of severe cGvHD, and that patients receiving 9/10 compared with 10/10 HLA allele-matched unrelated donors HSCT had a higher risk of cGvHD.

In another study, the use of PTCy in patients who received haplo HSCT led also to superior outcomes when compared with patients who received matched unrelated donor (MUD) HSCT with calcineurin inhibitors.

Given that another main strategy for GvHD prophylaxis is the use of anti-thymocyte globulin (ATG), a retrospective study compared these two prophylaxis regimens in adult patients with acute myeloid leukemia (AML) receiving allo-HSCT from HLA-identical siblings. Results supported the use of PTCy as an alternative option to ATG in the HLA-identical setting. A lower cumulative incidence of cGvHD was observed with the use of ATG but only when it was used in association with one additional immunosuppressive drug.

PTCy was also investigated in combination with ATG in patients who had received MUD transplants and mismatched unrelated donor (MMUD) transplants. This combination resulted in low rates of Grade III/IV aGvHD and cGvHD in patients who underwent MUD PBSCTs.

NK mediated T-cell inhibition

Interesting lessons could be learned from donor lymphocyte infusions (DLI) where GvHD represents the main toxicity.⁵ A way to improve GvHD is the use of sequential CTLA4Ig-primed DLI administered after allo-HSCT. CTLA4Ig attenuates T-cell activation by costimulation blockade but promotes mature natural killer (NK) cell proliferation. A study performed in patients with high-risk acute leukemia showed improved outcome with a low incidence of cGvHD with this approach.

Novel DLI approaches have been presented during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition: NEXI-001, an adoptive cellular therapy product containing leukemia-specific CD8+ T cells (NCT04284228); and prophylactic donor-derived IL-2 activated NK cell infusion from a matched sibling donor (NCT01853358). Results from phase I studies evaluating these new approaches show promising safety profile with no patients experiencing GvHD with NEXI-001, and four (one mild, two moderate, and one severe) out of 16 patients experiencing cGvHD with NK cell infusions (all patients recovered from their cGvHD).

Treg mediated T-cell inhibition

An impaired development of regulatory T cells (Tregs) after HSCT is associated with an increased incidence of GvHD. The use of Orca-T, an engineered Treg donor product, in patients with high-risk or active hematologic malignancies has demonstrated to effectively reduce the incidence of aGvHD and cGvHD compared with the current standard of care.

Conclusion

Transplantation of PBSC has increased worldwide because of faster engraftment and practicability compared with BM transplantation. However, the observed increase in GvHD with the use of PBSC has questioned the use of this stem cell source. Instead of returning to BM as preferred source for HSCT, efforts have been made to reduce the incidence of GvHD with new approaches that have demonstrated promising preliminary results.