Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapeutic option for a wide range of immune and hematologic malignant and non-malignant disorders. Once transplanted, allogeneic cells have to support myeloid repopulation and immunological reconstitution, but also need to become tolerant to the host via central or peripheral mechanisms to achieve the desired therapeutic effect. Peripheral tolerance after allogeneic HSCT may be achieved by several mechanisms, though blocking alloreactivity to the host human leukocyte antigens while preserving immune responses to pathogens and tumor antigens remains a challenge. Recently uncovered evidence on the mechanisms of post-HSCT immune reconstitution and tolerance in transplanted patients has allowed for the development of novel cell-based therapeutic approaches. These therapies are aimed at inducing long-term peripheral tolerance and reducing the risk of graft-vs-host disease (GvHD), while sparing the graft-vs-leukemia (GvL) effect. Thus, ensuring effective long term remission in hematologic malignancies. Today, haploidentical stem cell transplants have become a widely used treatment for patients with hematological malignancies. A myriad of ex vivo and in vivo T-cell depletion strategies have been adopted, with the goal of preventing GvHD while preserving GvL in the context of immunogenetic disparity. αβ T-cell/CD19 B-cell depletion techniques, in particular, has gained significant momentum, because of the high rate of leukemia-free survival and the low risk of severe GvHD. Despite progress, better treatments are still needed in a portion of patients to further reduce the incidence of relapse and achieve long-term tolerance. Current post-HSCT cell therapy approaches designed to induce tolerance and minimizing GvHD occurrence include the use of (i) γδ T cells, (ii) regulatory Type 1 T (Tr1) cells, and (iii) engineered FOXP3+ regulatory T cells. Future protocols may include post-HSCT infusion of allogeneic effector or regulatory T cells engineered with a chimeric antigen receptor (CAR). In the present review, we describe the most recent advances in graft engineering and post-HSCT adoptive immunotherapy.
Highlights
Successful allogeneic hematopoietic stem cell transplantation (HSCT) requires the development of immune tolerance toward both the donor and host allogeneic antigens
We showed that Vδ2 T cells from patients who received αβhaplo-HSCT expanded in vitro upon incubation with zoledronic acid (ZOL), which promoted the acquisition of an EM phenotype and potentiated the cytotoxic activity against primary leukemic blasts
A first clinical trial aimed at prevention of graft-vs-host disease (GvHD) and establishment of immunological tolerance after haplo-HSCT with purified CD34+ cells in adult with high risk leukemias was carried out using donor Tr1 cells specific for host alloantigens [73]
Summary
Successful allogeneic hematopoietic stem cell transplantation (HSCT) requires the development of immune tolerance toward both the donor and host allogeneic antigens. Manufacturing of a cell product containing γδ T-cell subsets with anti-infectious and anti-leukemia activity, but lacking regulatory function, could have future clinical applications in haplo-HSCT. High levels of IL10 production and presence of Tr1 cells were not detected in patients with complete donor chimerism, suggesting that chronic allo-antigen stimulation by mismatched host APCs plays a role in Tr1 cell induction in vivo [69].
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