The goal of all projects within our junior research group is to develop clinically effective, low toxicity, peptide-based immunotherapy approaches for the treatment of HM. The first critical issue is the selection of optimal antigen targets, which should show natural, high frequent and tumor-exclusive presentation on the cell surface of malignant cells and are recognized by patients T cells. Several studies have suggested neoepitopes arising from tumor-specific mutations as central specificities of checkpoint inhibitor induced T-cell responses in solid tumors. However, besides these neoantigens, several groups also described tumor-associated self-peptides that are able to induce peptide-specific T-cell responses and could be used as targets for peptide-based immunotherapy approaches. To identify tumor-associated self- and neoantigens we are using a direct method of HLA-presented peptide isolation and mass spectrometric analysis followed by various T-cell assays to prove the immunogenicity of our newly defined antigen targets. Current project are focusing on the identification of tumor-associated antigens for chronic myeloid leukemia (Wilhelm Sander grant), CD34+CD38- AML progenitor/tumor stem cells and premalignant and early stages of HM including monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma (SMM), myelodysplastic syndrome (MDS), Polycythemia vera and myelofibrosis.
The aim of these projects is to identify suitable adjuvants and immunomodulatory drugs for combination with peptide-based immunotherapy, which ideally reinforce peptide-specific T-cell responses and do not affect the immunopeptidome, i.e. robust presentation of peptide targets. Furthermore, some anti-cancer drugs might even induce novel treatment-associated peptides, which may represent interesting candidates for the improvement of immune control in HM. We are using an established in vitro treatment model to longitudinally and semi-quantitatively map the impact of different drugs on the immunopeptidome of HM using primary patient samples and cell lines. Cancer drugs of interest are for example demethylating agents, immune checkpoint inhibitors, HDAC inhibitors, TKIs and JAK2 inhibitors. Further more we analyze the positive and negative effects of standard anti-cancer drugs (e.g. TKIs, demethylating agents, JAK2 inhibitors, etc.) as well as potential adjuvants (imiquimod, synthetic lipopeptides) and immunomodulatory drugs (lenalidomide, checkpoint inhibitors) on T-cell proliferation and function.
The feasibility of translating our experimental data in clinical trials is demonstrated by our ongoing multi center patient-individualized peptide vaccination study for CLL patients iVAC-L-CLL01 (NCT02802943). All clinical studies are developed in close collaboration with Prof. Rammensee and Prof Stevanovic (Department of Immunology, Tübingen) and Prof. Salih (KKE Translational Immunology, Tübingen). The following study concepts are planned for the next years: