T cell receptor gene-therapy has entered the clinic and shown potential for successful cancer treatment. However, the clinical evaluation has also highlighted the need for selection of truly cancerspecific targets. Merkel cell carcinoma (MCC) is a highly aggressive skin cancer associated with Merkel cell polyomavirus (MCPyV). Due to the clear viral correlation CD8+ T cells specific for viral epitopes could potentially form cancer-specific targets in MCC patients. We have identified MCPyV specific T cells using a high-throughput platform for T-cell enrichment and combinatorial encoding offluorescence-labeled major histocompatibility complex (MHC) class I multimers. We identified 35 T cell epitopes among 398 MCPyV derived peptides analyzed. Strikingly, T-cell responses against the two oncogenic MCPyV proteins Large T antigen and small T antigen were exclusively present in blood of MCC patients when compared to healthy donors. We demonstrate both the processing and presentation of oncoprotein-derived epitopes, as well as lytic activity of specific T cells towards MHC matched MCC cells. Demonstrating the presence of oncoprotein-specific T cells among tumorinfiltrating lymphocytes ex vivo further substantiated the relevance of the identified epitopes. The viralepitopes represents specific targets and should be ideal for TCR-gene therapy approaches. We have isolated and sequenced MCPyV oncogenic protein specific T cell receptors and are currently testing in vitro transduction systems with the purpose of introducing the TCRs into human PBMC, injecting them into immune deficient NOG mice carrying HLA matched MCPyV positive tumor to investigate the tumor rejection capacity of these gene-modified T cells.
|Conference|| ICI 2016 International Congress of Immunology|
|Period||21/08/2016 → 26/08/2016|