HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse

Abstract

Posttransplant relapse is still the major cause of treatment failure in high-risk acute leukemia. Attempts to manipulate alloreactive T cells to spare normal cells while killing leukemic cells have been unsuccessful. In HLA-haploidentical transplantation, we reported that donor-derived T regulatory cells (Tregs), coinfused with conventional T cells (Tcons), protected recipients against graft-versus-host disease (GVHD). The present phase 2 study investigated whether Treg-Tcon adoptive immunotherapy prevents posttransplant leukemia relapse. Forty-three adults with high-risk acute leukemia (acute myeloid leukemia 33; acute lymphoblastic leukemia 10) were conditioned with a total body irradiation-based regimen. Grafts included CD34(+) cells (mean 9.7 × 10(6)/kg), Tregs (mean 2.5 × 10(6)/kg), and Tcons (mean 1.1 × 10(6)/kg). No posttransplant immunosuppression was given. Ninety-five percent of patients achieved full-donor type engraftment and 15% developed ≥grade 2 acute GVHD. The probability of disease-free survival was 0.56 at a median follow-up of 46 months. The very low cumulative incidence of relapse (0.05) was significantly better than in historical controls. These results demonstrate the immunosuppressive potential of Tregs can be used to suppress GVHD without loss of the benefits of graft-versus-leukemia (GVL) activity. Humanized murine models provided insights into the mechanisms underlying separation of GVL from GVHD, suggesting the GVL effect is due to largely unopposed Tcon alloantigen recognition in bone marrow.

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

“…55 Given the variety of immune cells contained in the apheresis product, many strategies have been developed in order to rationally select graft effectors and provide designed adoptive immunotherapies, especially in the haploidentical stem cell transplant setting. [56][57][58] In this scenario, Schumm et al 59 recently introduced an innovative approach of graft manipulation, which consist in depleting the leukapheresis product of only TCR αβ + T cells and CD19 + B cells, thus retaining large numbers of crucial immune effectors such as TCR γδ + T cells, NK cells and DCs; this method has been safely tested in a cohort of children by Locatelli and colleagues. 60 Although G-CSF mobilization is known to alter phenotype and cytokine polarization of transplanted immune cells, very few data are available on the impact of plerixafor on allogeneic graft cell subsets, as it is not approved for administration in healthy donors yet.…”

Next generation HLA-haploidentical HSCT

“…28 Therefore, as previously reported, 29 Tregs controlled the alloreactivity of up to 1 × 10 6 per kg T lymphocytes, which is about 2log more than the threshold dose for GvHD. Brunstein et al 31 who supplemented GvHD prophylaxis in double-unit UCB transplantation with ex vivo expanded polyclonal Tregs, also reported a significantly reduced incidence of grade 2-4 GvHD.…”

“…26 T cells harvested from the bone marrow of our humanized mice killed human leukemia cells and autologous PHA blasts in vitro, thus confirming their cytotoxic activity was preserved and indicating that alloantigen recognition underlay the GvL effect. 28 The GvL effect could also be related to Treg migratory properties, which are linked to homing molecule expression in diverse sites.…”

“…15,16,33 At a median follow-up of 46 months (range 18-65 months), only 2/41 evaluable patients have relapsed. 28 Both had NPM+Flt3+AML in molecular relapse at time of HSCT and had received transplants from non-NK alloreactive donors. The cumulative incidence of relapse was significantly lower than in historical controls (0.05 vs 0.21; P = 0.03).…”

“…26,27 Similarly, in humanized mouse models, human Treg-Tcon immunotherapy eradicated human primary myeloid leukemia and lymphoblastic leukemia cell lines without triggering GvHD. 28 These insights from animal models prompted us to evaluate the impact of Treg-Tcon adoptive immunotherapy in the clinical setting of HLA-haploidentical transplantation. We designed a haplo-transplantation protocol that focused on co-infusion of a high number of broad repertoire T cells and freshly isolated CD4+CD25+, FOXP3+ Tregs, without any post-transplant immunosuppression.…”