Discovering optimal targets for adoptive T-cell immunotherapy of leukemia (P4346)

Abstract

The main barrier in allogeneic hematopoietic cell transplantation is the risk of developing graft-versus-host disease. This can be prevented by the injection of CD8 T cells targeted to leukemia associated antigens (LAAs) or minor histocompatibility antigens (MiHAs). Several studies in humans have established the value of LAAs and MiHAs as target for immunotherapy on solid tumors and leukemia, respectively. Importantly, their therapeutic efficacy has never been assessed on a per antigen basis. Thus, our goal is to directly compare the therapeutic efficacy of T-cells targeted to LAAs or MiHAs expressed on EL4 cells. We selected 4 MiHAs and 4 LAAs and confirmed their immunogenicity by in vitro cytotoxicity assays. We evaluated the anti-leukemic activity of antigen-specific CD8 T cells in vivo. Notably, mice immunized against MiHAs showed enhanced survival compared to mice immunized against LAAs. We found that decreased survival of EL4 bearing mice cannot be explained by weaker MHC I/Peptide interactions. Interestingly, we showed that T cells specific for 4 LAAs and 1 MiHA are undetectable by flow cytometry and that the abundance of tetramer positive cells correlates strongly with survival of EL4 bearing mice. We propose that CD8 T cells, mainly targeted to LAAs, bind weakly to their MHC I/Peptide complexes, leading to decreased immunogenicity. We believe that the insights gained from our studies will serve as guide for selecting the best antigens for future clinical trials.