The long-term goal of this project is to establish a novel clinical platform for enhancing immune reconstitution, and more specifically, the graft vs leukemia (GvL) effect post-transplant via prophylactic infusion of ex-vivo co-stimulated allogeneic DLI to improve the outcome for patients with acute leukemia and myelodysplastic syndrome. This strategy is based on our hypothesis that activated donor T-cells given after donor chimerism is established, at a time of minimal residual disease (MRD), and in the absence of the inflammatory milieu of the early post-transplant period, will induce a more potent GvL effect without causing severe GvHD. This study will provide a foundation for efforts to implement tumor-specific adoptive cellular therapy, i.e., enhancing GvL without increasing GvHD.
Specific Aim 1 : Conduct a phase I clinical trial to confirm the feasibility and safety of delayed infusion of activated DLI after T-cell depleted non-myeloablative allogeneic stem cell transplantation in adult patients with high risk hematologic malignancies. The incidence and severity of graft vs host disease will be a primary endpoint.
Specific Aim 2 : Assess the impact of prophylactic activated DLI on tumor-specific cytotoxicity and immune reconstitution: 2a) Study T-cell responses to leukemia-specific antigen (autologous tumor), polyclonal stimuli (SEB, PMA), and recall antigens (CMV, EBV), to assess for the enhanced immune potential of donor T-cells before and after ex-vivo costimulation via functional analysis of donor T-cell function based on 3 complementary read-outs: (i) proliferation via CFSE flow cytometric assay, (ii) cytokine secretion via interferon gamma release (ELISPOT), and (iii) cytotoxicity via degranulation assay as a marker of specific target killing based on flow cytometric analysis of CD107a. 2b) Study T-cell proliferative responses (proliferation, cytokine secretion, cytotoxicity) to leukemia-specific antigen (autologous tumor), polyclonal stimuli (SEB, PMA), and recall antigens (CMV, EBV), to assess for enhanced immune reconstitution of recipient T-cells before and after infusions of ex-vivo costimulated donor cells via functional analysis of recipient T-cells using the assays outlined above at 5 time points; pre- transplant, approximately day+90 (pre pADLI #1), approximately day+160 (pre pADLI #2), day+270, and day+365. ? ? ?
| Kumar, Anita J; Hexner, Elizabeth O; Frey, Noelle V et al. (2013) Pilot study of prophylactic ex vivo costimulated donor leukocyte infusion after reduced-intensity conditioned allogeneic stem cell transplantation. Biol Blood Marrow Transplant 19:1094-101 |
| Powell Jr, Daniel J; Brennan, Andrea L; Zheng, Zhaohui et al. (2009) Efficient clinical-scale enrichment of lymphocytes for use in adoptive immunotherapy using a modified counterflow centrifugal elutriation program. Cytotherapy 11:923-35 |
