''Designed'' grafts for HLA-haploidentical stem cell transplantation

Today human leukocyte antigen-haploidentical transplantation is a feasible option for patients with high-risk acute leukemia who do not have matched donors. Whether it is T-cell replete or T-cell depleted, it is still, however, associated with issues of transplant-related mortality and posttrans-plant leukemia relapse. After reports that adoptive immunotherapy with T-regulatory cells controls the alloreactivityof conventional T lymphocytes in animal models, tomorrow’s world of haploidentical transplantation will focus on new “designed” grafts. They will contain an appropriate ratio of conventional T lymphocytes and T-regulatory cells, natural killer cells, gd T cells, and other accessory cells. Preliminary results of ongoing clinical trials show the approach is feasible. It is associated with better immune reconstitution and a quite powerful graft-versus-leukemia effect with a low incidence of graft-versus-host disease and no need for posttransplant pharmacological prophylaxis. Future strategies will focus on enhancing the clinical benefit of T-regulatory cells by increasing their number and strengthening their function

In vivo MRI measurement of microstructural constraints for direct drug delivery within the brain

Brain tissue microstructure may influence the efficient delivery of therapeutics within the brain. Diffusion Tensor Imaging (DTI) enables the depiction of tissue properties in vivo, and thus is potentially relevant for planning convection-enhanced delivery (CED) within the brain. We report on the quantitative assessment of the distribution of a Gadolinium solution infused by CED within the brain of a live ovine model. Infusate distributions were measured at multiple timepoints and compared to microstructural properties as depicted by DTI, thus demonstrating the impact of tissue features and catheter positioning on drug distribution in vivo

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

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 post-transplant 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 CD341 cells (mean 9.7 3 106 /kg), Tregs (mean 2.5 3 106/kg), and Tcons (mean 1.1 3 106 /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 ical 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. he benefits of graft-versus-leukemia (GVL) activity. Humanized murine models provided eparation of GVL fromGVHD, suggesting theGVL effect is due to largely unopposed Tcon Blood. 2014;124(4):638-644