Alpha/Beta T-Cell Depleted Grafts as an Immunological Booster to Treat Graft Failure after Hematopoietic Stem Cell Transplantation with HLA-Matched Related and Unrelated Donors

Abstract

Allogeneic hematopoietic stem cell transplantation is associated with several complications and risk factors, for example, graft versus host disease (GVHD), viral infections, relapse, and graft rejection. While high levels of CD3+ cells in grafts can contribute to GVHD, they also promote the graft versus leukemia (GVL) effect. Infusions of extra lymphocytes from the original stem cell donor can be used as a treatment after transplantation for relapse or poor immune reconstitution but also they increase the risk for GVHD. In peripheral blood, 95% of T-cells express the αβ T-cell receptor and the remaining T-cells express the γδ T-cell receptor. As αβ T-cells are the primary mediators of GVHD, depleting them from the graft should reduce this risk. In this pilot study, five patients transplanted with HLA-matched related and unrelated donors were treated with αβ T-cell depleted stem cell boosts. The majority of γδ T-cells in the grafts expressed Vδ2 and/or Vγ9. Most patients receiving αβ-depleted stem cell boosts increased their levels of white blood cells, platelets, and/or granulocytes 30 days after infusion. No signs of GVHD or other side effects were detected. A larger pool of patients with longer follow-up time is needed to confirm the data in this study.

CD34+ selected stem cell boosts can improve poor graft function after paediatric allogeneic stem cell transplantation

“…CD3/CD19 and TcRαβ depletion, which allow the retention of important mature T cell populations, such as TcRγδ and NK cells, known to play a role in underlying disease and infection control. There are few reports about the use of such techniques (Rådestad et al , ), and the indication for SCB is slightly different (poor immune reconstitution rather than PGF) but, together with our own findings, they suggest additional interactions between stem cells and already committed populations of precursors, which deserve further investigation.…”

“…Various graft manipulation procedures are currently available and are of high importance, especially for mismatched donors. Options include CD133 + or CD34 + positive selection of donor peripheral blood stem cells (PBSC) and, as recently reported, the use of CD3 + or TcRαβ T‐cell depletion (Rådestad et al , ). Here, we report on our single centre experience with CD34 + selected SCB from alternative donors (matched unrelated and mismatched, haploidentical related) for PGF treatment over a 15‐year period.…”

Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution

“…After HSCT, an increased number of gd T cells is associated with a better clinical outcome in terms of higher disease-free and event-free survivals (9,10,12,14), making these cells promising candidates for cellular therapy (39). As gd T cells exert a potent antileukemic effect (16) and can mediate a graft-versus-leukemia effect without causing GvHD (44), ongoing trials are investigating the benefits of grafts enriched in gd T cell numbers (13,14) and their role in donor lymphocyte infusion (45). The impact on outcome of gd T cell donor graft composition is most likely not solely related to the absolute number of gd T cells present in the graft, underlining the importance of a full qualitative characterization of these cells in the PBSC grafts.…”

Clinical applications of donor lymphocyte infusion from an HLA-haploidentical donor: consensus recommendations from the Acute Leukemia Working Party of the EBMT

“…102 Selective depletion of CD3 + αβ-TCR + T cells (thought to be the principal mediators of GvHD) to enrich DLI with CD3 + γδ-TCR + T cells and CD3 − CD56 + NK cells is also an attractive strategy to reduce the risk of GvHD while maintaining tumor alloreactivity. 103 Maschan et al infused low-dose (1x10 5 CD3 + cells/kg) CD45RA-depleted DLI (memory T cell) in 25 patients after TCR α/β-depleted haplo-HCT. The intervention was safe and associated with the expansion of cytomegalovirus-specific T cells in the recipients.…”