樹状細胞を利用した高齢者急性骨髄性白血病に対する 新規細胞免疫療法開発の試み

抄録

We conducted two clinical trials of dendritic cell (DC)-based immunotherapy for elderly patients with acute myeloid leukemia. In both trials, autologous DCs were generated by culturing monocytes which were obtained from patients after recovery of normal hematopoiesis by chemotherapy, in the presence of GM-CSF and IL-4. In the first trial, DCs pulsed with autologous apoptotic leukemic cells were administered intradermally together with OK-432 to induce maturation of DCs in vivo. Injection sites were pretreated with OK-432 to facilitate DCs to migrate to regional lymph nodes by local skin inflammation. In the second trial, DCs were pulsed with HLA-A^＊24:02-restricted WT1235-243 modified peptide and zoledronate to activate Vγ9Vδ2 T cells, which exert the enhancing effect on the T cell-activating capacity of DCs. DCs were matured with TNF-α and PGE₂ ex vivo, and administered intradermally and intravenously. In the first trial, two of four patients showed induction of anti-leukemic immune response. In one patient with HLA-A^＊24:02, CD8 T cell responses against HLA-A^＊24:02-restricted WT1 and hTERT peptides were detected by IFN-γ ELISPOT assay and HLA tetramer staining. These results demonstrate cross-presentation of leukemia antigens in vivo by DCs pulsed with apoptotic leukemic cells. In the second trial, two of three patients showed induction of WT1 modified peptide-specific immune response. Notably, a small fraction of WT1 modified peptide-specific T cells was cross-reactive to the WT1 natural peptide. Moreover, whereas most of the modified peptide-specific T cells disappeared shortly after completion of DC vaccination, T cells cross-reactive to the natural peptide persisted longer presumably owing to presentation of the natural peptide by leukemic cells in vivo. In both trials, inductions of anti-leukemic immune response were associated with longer periods of stable disease. DC-based immunotherapy for elderly patients with acute myeloid leukemia is feasible and safe, and has the potential to improve clinical outcome of these patients.