T-cell receptor mimic antibodies in hematological and solid malignancies: Identification of novel targets and implications for combined immunochemotherapy

• Applicant: Dr. Martin Klatt
• Subject Area: Hematology, Oncology ; Immunology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 358467622

Over the last years immunotherapies had a huge positive impact on cancer therapy. T-cell receptor mimic antibodies represent a novel, innovative and promising approach to expand the repertoire of these immunotherapies. By combining the specificity of a T-cell receptor to target a unique peptide presented on a distinct MHC with the therapeutic potency of regular monoclonal antibodies as well as BiTEs, such as Rituximab or Blinatumomab, TCRms have the potential to form a new class of highly specific, effective and hardly toxic immunotherapy. Recent publications by the Scheinberg Lab at the MSKCC demonstrated the immense potential of this approach in nude mouse xenograft models of different kind of malignancies. Therefore the Scheinberg lab established a perfect model for further investigations on these new therapeutics.One of the main goals in this research project will be the identification of more specifically selected target epitopes for TCRm therapy. Therefore, we want to isolate HLA-ligands directly from primary cancer tissues, tumor cell lines and peripheral blood mononuclear cells (PBMCs) from healthy donors. After the identification of the peptide sequence of the ligands by mass spectrometry we are able to appoint novel and hopefully truly tumor specific epitopes. By using this approach we aim to minimize potential side effects of TCRm treatment through cross reactions with healthy tissue cells and to facilitate the use of TCRms for early translational therapy. Considering epitope selection network analysis of HLA ligands will be performed in order to lighten identification of relevant T cell epitopes as recently published by Klatt et al.. Preliminary work of the Rammensee and Stevanovic Lab by colleagues and myself already showed encouraging results for detection of possible HLA ligands derived from AML, prostate cancer or renal cell carcinoma.A similar approach will be used for the identification of non HLA-A*02 restricted T cell epitopes from the well established tumor associated antigen WT1 to enlarge the potential therapeutic use of TCRms directed against this antigen which showed impressive results so far.All epitopes detected by aforementioned experiments will form the basis for the design of novel TCRms. Afterwards their efficacy will be analyzed in pre-established NSG-mouse xenograft tumor models.Additionally, combination therapies of e.g. TCRms with chemotherapeutics or tyrosine kinase inhibitors used at non-cytotoxic doses will be performed to check for improved potency by the TCRms through upregulation of MHC-molecules on the cell surface. Altogether, these projects aim to expand the applications of TCRms by establishing novel TCRms against different cancer epitopes and entities as well as to prepare TCRms for translational approaches by improving their specificity.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. David Scheinberg