Immune monitoring and TCR sequencing of CD4 T cells in a long term responsive patient with metastasized pancreatic ductal carcinoma treated with individualized, neoepitope-derived multipeptide vaccines: a case report
Katja Sonntag,1 Hisayoshi Hashimoto,1 Matthias Eyrich,2 Moritz Menzel,3 Max Schubach,4 Dennis Döcker,3 Florian Battke,3 Carolina Courage,5 Helmut Lambertz,6 Rupert Handgretinger,1 Saskia Biskup,3 and Karin Schilbach1,7,8
Department of Pediatric Hematology and Oncology, University Children’s Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany.
Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Medical Center Würzburg, Josef-Schneider Street 2, 97080, Würzburg, Germany.
Center for Genomics and Transcriptomics (CeGaT) GmbH and Practice for Human Genetics, Paul-Ehrlich-Straße 23, 72076, Tübingen, Germany.
Institute for Medical and Human Genetics, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
Folkhälsan Institute of Genetics, Haartmaninkatu 8, 00014, Helsinki, Finland.
Klinikum Garmisch-Partenkirchen GmbH, Zentrum für Innere Medizin, 82467, Garmisch-Partenkirchen, Germany.
University Children’s Hospital, University Medical Center Tübingen, Hoppe-Seyler-Street 1, 72076, Tübingen, Germany. Karin.Schilbach@med.uni-tuebingen.de.
Cancer vaccines can effectively establish clinically relevant tumor immunity. Novel sequencing approaches rapidly identify the mutational fingerprint of tumors, thus allowing to generate personalized tumor vaccines within a few weeks from diagnosis. Here, we report the case of a 62-year-old patient receiving a four-peptide-vaccine targeting the two sole mutations of his pancreatic tumor, identified via exome sequencing.
Vaccination started during chemotherapy in second complete remission and continued monthly thereafter. We tracked IFN-γ+ T cell responses against vaccine peptides in peripheral blood after 12, 17 and 34 vaccinations by analyzing T-cell receptor (TCR) repertoire diversity and epitope-binding regions of peptide-reactive T-cell lines and clones. By restricting analysis to sorted IFN-γ-producing T cells we could assure epitope-specificity, functionality, and TH1 polarization.
A peptide-specific T-cell response against three of the four vaccine peptides could be detected sequentially. Molecular TCR analysis revealed a broad vaccine-reactive TCR repertoire with clones of discernible specificity. Four identical or convergent TCR sequences could be identified at more than one time-point, indicating timely persistence of vaccine-reactive T cells. One dominant TCR expressing a dual TCRVα chain could be found in three T-cell clones. The observed T-cell responses possibly contributed to clinical outcome: The patient is alive 6 years after initial diagnosis and in complete remission for 4 years now.
Therapeutic vaccination with a neoantigen-derived four-peptide vaccine resulted in a diverse and long-lasting immune response against these targets which was associated with prolonged clinical remission. These data warrant confirmation in a larger proof-of concept clinical trial.