H1-Parvovirus induzierter immunogener Zelltod: potenzielle Basis für eine neue Chemo-Virotherapie des Pankreaskarzinoms
Zusammenfassung der Projektergebnisse
Pancreatic ductal adenocarcinoma (PDAC) is a severe gastrointestinal malignancy with very poor prognosis for the patients, due to late diagnosis and lack of effective therapies. There is a clear demand to develop alternative approaches for the treatment of PDAC besides standard surgery and radio/chemotherapy. Based on our previous work, we concluded that direct oncolytic activity is required but not sufficient for eradication of tumors by combined H1-PV and Gemzar® treatment (chemovirotherapy, CVT); the concomitant induction of the immune response is crucial. As a possible mechanism which may underlie collateral triggering of long-term anticancer immunity by CVT, we suggested an induction of immunogenic cell death (ICD). For that, tumor cell should release immune system activators such as HMGB1, CRT, ATP and uric acid while dying. These ICD-determinants ensure attraction and activation of antigen-presenting cells consequently enabling cross-presentation of tumor antigens and cross-priming of cytotoxic effectors lymphocytes (CTL) in appropriate environment. The main objective of the current project was to prove these assumptions and to create a basis to exploit H-1PV/GEM combination in clinically-relevant protocols. Our results show that the H1-parvovirus in mono or combination therapy with the chemotherapeutic Gemzar can be used for effective PDAC treatment. We proved the efficiency in vitro in pancreatic cancer cell lines as well as in vivo in rodent models. We also proved that immunemodulating effects are of the same importance as the direct viral oncolysis. Although CVT induced a very poor CRT response, the abundant virus-mediated secretion of another ICD-determinant, alarmin HMGB1, emerged as an active, death-independent/apoptosis-compatible process, which we were first to describe. Cytostatic/irradiation and parvovirus showed a distinctive pattern of compatibility, whereby reciprocation compensated mutual shortcomings or adverse side effects. Our project resulted in the establishment of a unique primary pancreatic cancer cell line (ASAN-PaCa); publications in scientific journals; and patents, which were out-licensed to an industrial partner, which currently delivers the parvovirus as a drug for a clinical trial aiming treatment of the patients with pancreatic cancer.
Projektbezogene Publikationen (Auswahl)
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(2010) Immune cells participate in the oncosuppressive activity of parvovirus H-1PV and are activated as a result of their abortive infection with this agent, Cancer biology & therapy 10, 1280-1289
Grekova, S., Aprahamian, M., Giese, N., Schmitt, S., Giese, T., Falk, C. S., Daeffler, L., Cziepluch, C., Rommelaere, J., and Raykov, Z.
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(2011) Interferon gamma improves the vaccination potential of oncolytic parvovirus H-1PV for the treatment of peritoneal carcinomatosis in pancreatic cancer, Cancer biology & therapy 12, 888-895
Grekova, S. P., Aprahamian, M., Daeffler, L., Leuchs, B., Angelova, A., Giese, T., Galabov, A., Heller, A., Giese, N. A., Rommelaere, J., and Raykov, Z.
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(2013) Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas, EMBO molecular medicine 5, 1537-1555
Li, J., Bonifati, S., Hristov, G., Marttila, T., Valmary-Degano, S., Stanzel, S., Schnolzer, M., Mougin, C., Aprahamian, M., Grekova, S. P., Raykov, Z., Rommelaere, J., and Marchini, A.
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(2013) TLR-9 contributes to the antiviral innate immune sensing of rodent parvoviruses MVMp and H-1PV by normal human immune cells, PloS one 8, e55086
Raykov, Z., Grekova, S. P., Horlein, R., Leuchs, B., Giese, T., Giese, N. A., Rommelaere, J., Zawatzky, R., and Daeffler, L.
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(2014) Complementary induction of immunogenic cell death by oncolytic parvovirus H-1PV and Gemzare in pancreatic cancer, Journal of virology 88, 5263-5276
Angelova, A. L., Grekova, S. P., Heller, A., Kuhlmann, O., Soyka, E., Giese, T., Aprahamian, M., Bour, G., Ruffer, S., Cziepluch, C., Daeffler, L., Rommelaere, J., Werner, J., Raykov, Z., and Giese, N. A.
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(2014) Genomic CpG Enrichment of Oncolytic Parvoviruses as a Potent Anticancer Vaccination Strategy for the Treatment of Pancreatic Adenocarcinoma. J Vaccines Vaccin, 5:2
Grekova, S. P., Aprahamian, M., Giese, N. A., Bour, G., Giese, T., Grewenig, A., Leuchs, B., Horlein, R., Heller, A., Angelova, A. L., Rommelaere, J. and Raykov, Z.
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(2016) Establishment and Characterization of a Novel Cell Line, ASAN-PaCa, Derived From Human Adenocarcinoma Arising in Intraductal Papillary Mucinous Neoplasm of the Pancreas, Pancreas 45, 1452-1460
Heller, A., Angelova, A. L., Bauer, S., Grekova, S. P., Aprahamian, M., Rommelaere, J., Volkmar, M., Janssen, J. W., Bauer, N., Herr, I., Giese, T., Gaida, M. M., Bergmann, F., Hackert, T., Fritz, S., and Giese, N. A.
