Escape of Minor Histocompatibility Antigen-Restricted Anti-Leukemia Immunity Associated with Loss of Specific HLA-I Locus Expression in a Leukemia Patient after an Intensive Immunotherapy.

Differential graft versus host response after bone marrow transplantation (BMT) is key to leukemia patient survival. The development of specific graft versus leukemia response targeting tissue-specific minor histocompatibility antigens (mHAgs) is a novel therapeutic approach to treating hematopoietic malignancies. A pilot intensive immune cell therapy was applied to an acute myeloid leukemia (AML) patient who relapsed around day 43 after receiving unrelated allogeneic BMT with three allele disparities for HLA-A, C and DQB1. The patient received more than thirty infusions of dendritic cell-co-cultured donor-derived immune cells including cytotoxic T lymphocytes (CTL) generated against AML lysate-pulsed dendritic cells (DC), AML-DC fusion, and DC pulsed with HLA-A*2402-restricted ACC1Y mHAg epitope. The latter was expressed by recipient but not by donor hematopoietic cells. ACC1Y-peptide-major histocompatibility complex (MHC) multimer staining detected CTL in the patients peripheral blood at different time points during treatment. Four months after the first mHAg-CTL infusion, CTL-resistant AML cells were detected in relapsed pleural effusion and peripheral blood. Further analysis of the relapsed AML cells revealed complete loss of surface class I HLA-A*2402 and class II HLA molecules. Although the AML-specific immune cells were effective in killing the original AML in CTL assays in vitro, the late relapsed AML became resistant to the early AML-primed CTL. This result suggests that rapidly evolving AML cells may escape the intensive anti-leukemia allo-immune pressure including the mHAg-specific CTL through selective loss of A*2402 expression - the ACC1Y-restricted HLA locus. As the patient suffered ongoing multi-focal extramedullary relapse in muscles, sub-mucosal tissue, intestine, spinal cord, and brain, rare cancer cells resistant to mHAg-specific CTL could evolve quickly. Our study indicates that immune escape through diminished HLA expression, which resulted in lack of cancer cell killing by AML-specific immune cells, including the mHAg-restricted CTL, had developed during the therapy. Therefore, leukemia patients with high load of AML or multi-focal extramedullary relapse may not endure prolonged benefit from a single arm immune cell therapy.