CANCER VIROTHERAPY

Head: Prof. Dr. Jean Rommelaere

The concept

Research conducted by the CANCER VIROTHERAPY team focuses on viruses belonging to the parvovirus family. These prefer to multiply in dividing tumor cells. By doing so, they can inhibit tumor growth by directly causing the tumor cells to die or making them more receptive to various therapeutic treatments. Our effort is to understand the underlying mechanism of this effect and put it to the clinical test.
The research program is based on the ability of certain autonomous parvoviruses (PV) to prevent the formation, inhibit the growth, or cause the regression of cancers in animal models. These oncosuppressive properties rely at least partly on the preferential multiplication of PV in certain tumours (oncotropism) and on the cytopathic effects they exert (oncolysis). Furthermore, innate and adaptive immune responses contribute to the anticancer activity of PV. The program exploits experimental systems that have been developed in the Division so as to address issues directly related to clinical applications of PV. Part of the research is focused on basic scientific investigations aiming at understanding the molecular mechanisms of PV cytotoxicity and immune-modulation, with focus on the ability of PV to circumvent tumor cell resistance to conventional anti-cancer treatments and serve as adjuvants in cancer immunotherapy protocols. Moreover the program involves (i) the preclinical evaluation of the antitumour activity of PV (vectors), and (ii) the transposition of the most advanced candidates to a clinical setting.

Parvovirus H-1 clinical trials: accompanying research

Group leader: Dr. Assia Angelova, PhD

Contact:

Assia Angelova, PhD

Tel. +49 6221 42 49 64
Fax +49 6221 42 49 62
Email: Assia Angelova

Glioblastoma multiforme (GBM) is the most malignant type of brain tumor, with median survival of less than 15 months after initial diagnosis. Current treatment options do not achieve a major improvement, and the prognosis for GBM patients still remains very poor. Research activities performed in the Division “Tumor Virology” have demonstrated that the oncolytic parvovirus H-1 (H-1PV) exerts striking oncotoxic and oncosuppressive effects in in vitro and in vivo preclinical GBM models.
In 2011, a phase I/IIa clinical trial (ParvOryx01) was launched with the aim to evaluate the safety, tolerability and efficacy of H-1PV therapy in patients with recurrent GBM. This is the first clinical trial with a replication-competent oncolytic virus in Germany, and the first one to involve an oncolytic parvovirus. Eligible patients are subdivided into two treatment arms. Patients are subjected to either an intratumoral (arm 1) H-1PV injection or a systemic (arm 2) virus administration, followed by tumor resection ten days after treatment and  repeated H-1PV inoculation into the walls of the resection cavity. Our team is involved in both preclinical data generation and ParvOryx01 trial-accompanying research. Our main activities include: (1) detection of H-1PV replication and expression markers in patient-derived GBM material (resected tumor) using fluorescence in situ hybridization (FISH), immunofluorescence (IF) and immunohistochemistry (IHC); (2) phenotypic characterization of  H-1PV target cells within the highly heterogeneous GBM cellular environment; (3) evaluation of H-1PV intratumoral distribution after local or systemic virus administration; (4) analysis of H-1PV-induced GBM immune cell infiltration, including (i) detection of immune cell type-specific markers, and (ii) assessment of immune cell activation status.
First intriguing results have already been obtained, demonstrating (i) viral mRNA synthesis and protein expression in injected tumors; (ii) virus expression at tumor sites distant from the injection site; (iii) H-1PV ability to cross the blood-brain-barrier and to penetrate the tumor after a systemic virus administration; and (iv) virus dose-dependent GBM necrosis and accumulation of tumor-infiltrating immune cells.
We believe that further analysis of these surrogate markers of efficiency will warrant the extension of parvovirus clinical studies to subsequent phases and to non-CNS tumor entities.

Team members:

Dr. Assia Angelova
Dr. Karsten Geletneky
Alexandra Just

Selected Publications from 2009-2014

1.    Angelova, A., Aprahamian, M., Grekova, S., Hajri, A., Leuchs, B., Giese, N., Herrmann, A., Dinsart, C., Balboni, G., Rommeleare, J* and Raykov, Z*. (2009)
        Improvement of gemcitabine-based therapy of pancreatic carcinoma by means of     oncolytic      parvovirus H-1PV.
        Clinical Cancer Research, 15, 511-519.
2.         Angelova, A., Aprahamian, M., Balboni, G., Delecluse, H.-J., Feederle, R., Kiprianova, I., Grekova,     S., Galabov, A.S., Witzens-Harig, M., Ho, A.D., Rommelaere, J.* and Raykov, Z.* (2009)
        Oncolytic rat parvovirus H-1PV, a candidate for the treatment of human lymphoma: in vitro and     in vivo studies.
        Molecular Therapy, 17, 1164-1172.
3.    Geletneky, K., Kiprianova, I., Ayache, A., Koch, R., Herrero Y Calle, M., Deleu, L., Sommer, C., Thomas, N., Rommelaere, J.* and Schlehofer, J.R.* (2010)
    Regression of advanced rat and human gliomas by local or systemic treatment with oncolytic  parvovirus H-1 in rat models.
    Neuro-Oncology, 12, 804-814.
4.    Bhat, R., Dempe, S., Dinsart, C. and Rommelaere, J. (2011)
    Enhancement of NK cell anti-tumour responses using an oncolytic parvovirus.
    International Journal of Cancer, 128, 908-919.
5.    Kiprianova, I., Thomas, N., Ayache, A., Fischer, M., Leuchs, B., Klein, M., Rommelaere, J. and Schlehofer, J.R. (2011)
    Regression of glioma in rat models by intranasal application of parvovirus H-1.
    Clinical Cancer Research, 17, 5333-5342.
6.        Grekova, S., Aprahamian, M., Daeffler, L., Leuchs, B., Angelova, A., Giese, T., Galabov, A.S.,     Heller, A., Giese, N.A., Rommelaere, J. and Raykov, Z. (2011)
        Interferon-gamma improves the vaccination potential of oncolytic parvovirus H-1PV for the     treatment of peritoneal carcinosis in pancreatic cancer.
    Cancer Biology and Therapy, 12, 889-895.
7.        Geletneky, K., Huesing, J., Rommelaere, J., Schlehofer, J.R., Dahm, M., Krebs, O., von Knebel     Doeberitz, M., Huber, B. and Hajda, J. (2012)
        Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration     of parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma     multiforme: ParvOryx01 protocol.
        BioMed Central Cancer, 12:99, DOI: 10.1186/1471-2407-12-99.
8.        Grekova, S.P., Raykov, Z., Zawatzky, R., Rommelaere, J. and Koch, U. (2012)
        Activation of a glioma-specific immune response by oncolytic minute virus of mice infection.
        Cancer Gene Therapy, 19, 468-475.
9.        Bhat, R. and Rommelaere, J. (2013)
    NK cell-dependent killing of colon carcinoma cells is mediated by natural cytotoxicity receptors     (NCRs) and stimulated by an oncolytic virus.
    BioMed Central Cancer, 13: 367, DOI: 10.1186/1471-2407-13-367.
10.     Angelova, A., Grekova, S., Heller, A., Kuhlmann, O., Soyka, E., Giese, T., Aprahamian, M., Bour, G., Rüffer, S., Cziepluch, C., Daeffler, L., Rommelaere, J., Werner, J., Raykov, Z. and Giese, N. (2014).
    Complementary induction of immunogenic cell death by oncolytic parvovirus H-1PV and gemcitabine in pancreatic cancer.
Journal of Virology, 88, 5263-5276.

        … and 9 granted patents









Pediatric virotherapy: Oncolytic parvoviruses for the treatment of malignant diseases occurring in childhood and adolescence

Group leader: Dr. Jeannine Lacroix

Contact:

Jeannine Lacroix, MD

Tel. +49 6221 5636238
FAX +49 6221 42 49 62
Email: Jeannine Lacroix

OUR WORK IS FOCUSED ON THE PRE-CLINICAL EVALUATION OF THE USE OF PARVOVIRUS H-1 AS A NOVEL THERAPEUTIC APPROACH IN PEDIATRIC ONCOLOGY. CURRENT RESEARCH PROJECTS

  1. Systematic in vitro screening of the cytotoxic efficacy of H-1PV in pediatric tumor cells
    To assess the potential benefit of pediatric patients from H-1V treatment a systematic, ongoing  in vitro screening is performed. To date, it includes more than 30 pediatric medulloblastoma, glioblastoma, neuroblastoma, Ewing’s sarcoma and osteosarcoma cell lines.
  2. Preclinical studies on the therapeutic efficacy of parvovirus H-1 (H-1PV) to brain tumor-initiating cells
    Despite multi-modal treatment concepts including surgery, radiation, and chemotherapy malignant brain tumors are characterized by an extremely bad prognosis. Thus, pre-clinical and clinical research focuses on new therapeutic approaches, such as oncolytic virotherapy. Based on extensive pre-clinical studies in vitro and in vivo, a phase I/IIa clinical trial for the application of parvovirus H-1 in adult glioblastoma patients has been initiated in October 2011. In children medulloblastoma is the most frequent malignant brain tumor, with subgroups of high-risk patients suffering from extremely poor prognosis. Here, the stage of development is still at a pre-clinical level.
    Clinical relapse of brain tumors has been hypothesized to originate from brain tumor-initiating cells resistant to conventional treatment. In order to assess the efficacy of H-1PV to induce oncolysis in recurrent brain tumors we systematically address this question using a panel of high-grade glioma neurosphere cultures. These cultures were obtained from collaboration partners who established them from primary tumor material.
    One focus of our current research is to confirm that H-1PV is able to infect, to replicate in and to selectively kill brain tumor-initiating cells in vitro and in appropriate xenograft-bearing animal models and to elucidate the mechanisms which enable H-1PV to induce these effects.
  3. Optimization strategies for the application of H-1PV in a clinical setting
    Since the state of pre-clinical research is most advanced for neuroblastoma we use cell culture and animal models for high-risk neuroblastoma to
    • optimize the mode of application of H-1PV
    • further increase the therapeutic efficacy by identification of the most promising combination treatment approaches (cytostatic drugs, epi-genetic modulators)
    • identify markers predictive for the response to parvovirotherapy

FUTURE PROJECTS AND GOALS

Basic research: Beyond the ongoing research projects described, we have started new projects in order to gain insights into the mechanisms of virus induced cytotoxicity to embryonic tumors of the nervous system and tumor- initiating cells derived thereof. In collaboration with the Division Pediatric Neurooncology (DKFZ) and the siRNA screening facility  (Bioquant), we aim to characterize target genes of viral proteins inducing fatal dysregulations in the metabolism of these malignant cells using high throughput technologies such as expression analysis by microarrays and  siRNA exprression.
Clinical research: Based on pre-clinical in vivo proof of concept experiments we aim in the preparation of a clinical phase I/IIa clinical trial on pediatric patients with primary progressive or recurrent embryonic tumors of the nervous system in the framework of cooperations with ORYX GmbH & Co. KG and the Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University Hospital Heidelberg.

PUBLICATIONS

  1. Lacroix, J., Schlund, F., Adolph, K., Leuchs, B., Hielscher, T., Rommelaere, J., Schlehofer, J.R., Pfister, S.M., Witt, O., Witt, H. (2014). Oncolytic effects of Parvovirus H-1 in medulloblastoma are associated with repression of master regulators of early neurogenesis. Int. J. Cancer, 134: 703–716.
  2. Nüesch, J.P.F., Lacroix, J., Marchini, A., Rommelaere, J. (2012). Rodent parvoviruses: mechanisms of oncolysis and prospects for clinical cancer treatment. Clin Cancer Res. 2012 Jul 1;18(13): 3516-23
  3. Lacroix, J., Leuchs, B., Li J., Hristov, G., Deubzer, H.E., Kulozik, A. E., Rommelaere, J., Schlehofer, J. R., Witt, O. (2010). Parvovirus H-1 induces cytotxic effects on human neuroblastoma cells. Int. J. Cancer, 127: 1230–1239.
  4. Lacroix, J., Witt, O., Schlehofer, J. R., and Rommelaere J. (2010), Therapeutic exploitation of oncolytic viruses in pediatric oncology. Drugs of the Future 35 (12): 1015-1027.

FUNDING

ORYX GmBH & Co. KG
Deutsche Krebshilfe e. V.
Wilhelm Sander-Stiftung
Jona Viskorf-Siftung
COLLABORATIONS
Dr. Holger Erfle, Bioquant, Heidelberg
Dr. Ina Oehme, Dr. H. Deubzer, Dr. Till Milde, Prof. Olaf Witt, Clinical Cooperation Unit Pediatric Oncology, DKFZ, Heidelberg
Prof. Christel Herold-Mende, Dept. of Neurosurgery, University of Heidelberg
PD Frank Westermann, Dept. Neuroblastoma Genetics, DKFZ Heidelberg
Dr. Hendrik Witt, Prof. Dr. Stefan Pfister, Div. Pediatric Neurooncology, DKFZ, Heidelberg

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