Ex-Vivo UVA Treated Donor T-Cells for the Induction of Graft Versus Leukemia Effect in Murine Model and Clinical Application

Donor lymphocyte infusion (DLI) is a powerful immune-manipulation for the induction of Graft-vs-Leukemia (GVL) effect, but it is associated with high incidence of Graft-vs-host disease (GVHD). Furthermore, the use of DLI across MHC mismatched transplantation is almost infeasible. Extra corporal photochemotherapy for the treatment of GVHD involves extra corporal exposure of peripheral blood mononuclear cells to photoactivated 8-methoxypsorelen (8-MOP) followed by re-infusion of the treated cells. Based on the immunomodulatory effects of 8-MOP and UVA irradiation we investigated ex-vivo similar treatment of donor cells prior to cell therapy in post-transplant murine model. F₁ leukemic (BCL1) recipients exposed to total body irradiation followed by bone marrow transplantation (BMT) (C57BL/6→F₁). Donor splenocytes incubated with 8-MOP and 10 minuets exposure to UVA irradiation were administrated twice a week for the first 21 days post-BMT. Irradiated hosts inoculated with BCL₁ and C57BL/6 cells were examined for the presence of donor cells using fluorescence-activated cell sorting analysis. At 4–6 weeks after BMT chimerism analysis revealed a ratio of 84–91% donor cells. Murine blood cells were tested for Minimal residual disease (MRD) by BCL₁- specific PCR for detection of dormant BCL1 at 2 months after BMT. In comparison with the control group, DLI with ex vivo 8-MOP UVA treated splenocytes reduced GVHD and retained GVL effect. In vitro secretion of interferon gamma by treated cells was reduced only by 50%.

Clinical application of this method was performed in 4 high-risk patients after stem cell transplantation from haploidentical related donors:

The potential of Ex-Vivo 8-MOP UVA DLI treated cells should further be investigated for induction of GVL w/o GVHD, to improve chimerism and for anti viral therapy (CMV, EBV and PTLD - Post Transplant Lymphoproliferative Disorders)