Clinical Research Papers:
Immunological data from cancer patients treated with Ad5/3 E2F Δ24 GMCSF suggests utility for tumor immunotherapy
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Otto Hemminki1, Suvi Parviainen1, Juuso Juhila1, Riku Turkki2, Nina Linder2, Johan Lundin2,3, Matti Kankainen4, Ari Ristimäki5, Anniina Koski1, Ilkka Liikanen1, Minna Oksanen1, Dirk M. Nettelbeck6, Kalevi Kairemo7, Kaarina Partanen7, Timo Joensuu7, Anna Kanerva1,8, Akseli Hemminki1,7,9
1Cancer Gene Therapy Group, Transplantation Laboratory & Haartman Institute, University of Helsinki, Helsinki, Finland
2Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland
3Division of Global Health/IHCAR, Karolinska Institutet, Stockholm, Sweden
4CSC - IT Center for Science Ltd, Helsinki, Finland
5Department of Pathology, HUSLAB and Haartman Institute, Helsinki, University Central Hospital and Genome-Scale Biology, Research Programs Unit, University of Helsinki, Helsinki, Finland
6German Cancer Research Center (DKFZ), Heidelberg, Germany
7Docrates Cancer Center, Helsinki, Finland
8Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland
9TILT Biotherapeutics Ltd, Helsinki, Finland
Akseli Hemminki, e-mail: [email protected]
Keywords: Oncolytic, immunotherapy, cancer, ATAP
Received: September 17, 2014 Accepted: December 14, 2014 Published: February 24, 2015
Oncolytic viruses that selectively replicate in tumor cells can be used for treatment of cancer. Accumulating data suggests that virus induced oncolysis can enhance anti-tumor immunity and break immune tolerance. To capitalize on the immunogenic nature of oncolysis, we generated a quadruple modified oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor (GMCSF). Ad5/3-E2F-Δ24-GMCSF (CGTG-602) was engineered to contain a tumor specific E2F1 promoter driving an E1 gene deleted at the retinoblastoma protein binding site (“Δ24”). The fiber features a knob from serotype 3 for enhanced gene delivery to tumor cells. The virus was tested preclinically in vitro and in vivo and then 13 patients with solid tumors refractory to standard therapies were treated. Treatments were well tolerated and frequent tumor- and adenovirus-specific T-cell immune responses were seen. Overall, with regard to tumor marker or radiological responses, signs of antitumor efficacy were seen in 9/12 evaluable patients (75%). The radiological disease control rate with positron emission tomography was 83% while the response rate (including minor responses) was 50%. Tumor biopsies indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication.
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