Targeting Late Relapsed Acute Myeloid Leukemia Cells by Cytotoxic T Cells Generated from Late but Not Early Leukemic Antigen-Presenting Dendritic Cells.

Cancer-specific cytotoxic T lymphocytes (CTL) have great potential in cancer immunotherapy. We performed a longitudinal study of CTL primed with dendritic cells (DC) exposed to leukemic antigens or DC directly differentiated from leukemic cells in an acute myeloid leukemia (AML) patient. The patient received three HLA locus-mismatched allogeneic bone marrow transplantation, relapsed around day 43, and after a brief remission, suffered an ongoing multi-focal extramedullary relapse. CTL generated against AML cells early during the course of disease (early-AML) effectively targeted the early-AML cells as demonstrated by in vitro CTL assays. The patient received multiple infusions of immune cells specific to the early-AML cells in a pilot trial. While the patient established stable remission in the peripheral blood, extensive extramedullary relapse had occurred. The CTL prepared from DC exposed to the early-AML cells failed to target the late relapsed AML (late-AML) cells isolated from pleural effusion and peripheral blood. Further characterization of the late-AML cells showed complete and partial loss of class II and class I HLA expression, respectively. Interestingly, CTL prepared from the late-AML-derived DC were able to kill the late relapsed cancer cells. This result suggests that the late-AML cells, although escaped from the early-AML-derived CTL, expressed novel immunogenic leukemic antigens. It appeared that selective growth of AML cells resistant to the early-AML-specific immune cells had occurred in vivo. However, CTL primed with the late-AML-derived DC were able to kill the late relapsed cancer cells in vitro. Thus, AML could evolve in vivo under active immunotherapy, but this may be coped with preparation of cancer-specific immune cells using the late-AML cells.