Immunopeptidomics - Development of therapeutic vaccines for the treatment of leukemia

Abstract

With the development and clinical success of immune checkpoint inhibitors, T-cell-based immunotherapy has been revolutionized. Therefore, in recent years special emphasis was placed on the identification of the target structures of the anti-tumor T-cell responses. These target structures are represented by tumor-associated or tumor-specific antigens presented on the surface of tumor cells via human leukocyte antigen (HLA) molecules. Further, the tremendous evolving field of mass spectrometry enables nowadays the direct identification of naturally presented HLA ligands from primary human samples in undreamt depth. This thesis aims to provide an insight into the rapidly developing field of mass spectrometry-based immunopeptidomics and the development of T cell based immunotherapeutic approaches for leukemia patients. For chronic lymphocytic leukemia (CLL) we performed a longitudinal study on the influence and effect of lenalidomide on the immunopeptidome of primary CLL cells. Mass spectrometry-based profiling identified only minor effects on HLA-restricted peptide presentation and confirmed stable presentation of previously described CLL-associated antigens under lenalidomide treatment. Therefore, lenalidomide was validated as suitable combination partner for tailored T-cell-based immunotherapeutic approaches in CLL patients. For chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), we applied a mass spectrometry-based approach to identify naturally presented, HLA-restricted leukemia-associated peptides, respectively. Therefore, we utilized a comparative profiling approach using a comprehensive dataset of different benign tissues. Functional characterization revealed spontaneous T-cell responses against the novel identified CML- and AML-associated peptides in patient samples and their ability to induce multifunctional and cytotoxic antigen-specific T cells. These antigens are thus prime candidates for T cell-based immunotherapeutic approaches for CML and AML patients.