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
Authors
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.
- Corresponding author.
Abstract
BACKGROUND:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
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.
