DFG2

HLA-Ligandomanalyse des Multiplen myeloms - Identifizierung neuer Myelom-assoziierter Antigene für eine Peptid-basierte Immuntherapie

01/02/2020 to 31/01/2023

Antigen-specific, T cell-based immunotherapies for multiple myeloma (MM) are on advance, further improving the outcome of this still incurable disease. The main prerequisites for the clinically effective application of such immunotherapy concepts is the identification and characterization of suitable MM-associated antigens, as well as an intact T-cell compartment capable to generate antigen-specific T-cell responses. While the repertoire of feasible extracellular membrane antigens is limited, HLA-dependent antigens derived from intracellular proteins or domains, which are processed and presented on the surface of tumor cells via HLA molecules provide a huge selection of potential tumor-associated antigens. Thus, in the first funding period of this project we characterized the naturally presented immunopeptidome of MM using a mass spectrometry-based approach and characterized several novel non-mutated myeloma-associated antigens. We further identified for the first time so called “treatment-associated” antigens that are induced by specific MM drugs like for example proteasome inhibitors, and therefore might represent highly promising targets for the development of combinatorial immunotherapies. Within the second funding period of this project we aim to expand the selection of naturally presented MM-associated T-cell epitopes, based on the characterization of (i) mutation-derived HLA ligands, (ii) treatment-associated HLA ligands and (iii) intracellular domain-derived HLA ligands of MM-associated membrane antigens. Further, as profound immune defects in established MM disease might hamper the induction of clinically effective T-cell responses, we aim to address this issue in two ways in this project. At first, we will characterize the immunopeptidome of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM), and its alteration during disease progression, as these preliminary stages of MM disease show a more intact ratio of functional T cells to MM cells and might more effectively be targeted by T-cell based immunotherapy approaches. Second, we will analyze therapeutic modulations of the T-cell compartment, using immunomodulatory drugs, immune checkpoint inhibitors and the CD38 antibody daratumumab, to overcome the immune defects in MM and optimize antigen-specific T-cell responses.