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Oncolytic adenovirus and doxorubicin‐based chemotherapy results in synergistic antitumor activity against soft‐tissue sarcoma
Author(s) -
Siurala Mikko,
Bramante Simona,
Vassilev Lotta,
Hirvinen Mari,
Parviainen Suvi,
Tähtinen Siri,
Guse Kilian,
Cerullo Vincenzo,
Kanerva Anna,
Kipar Anja,
VähäKoskela Markus,
Hemminki Akseli
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29048
Subject(s) - doxorubicin , ifosfamide , oncolytic virus , soft tissue sarcoma , oncolytic adenovirus , cancer research , sarcoma , medicine , hamster , pharmacology , cell culture , chemotherapy , biology , pathology , tumor cells , etoposide , genetics
Despite originating from several different tissues, soft‐tissue sarcomas (STS) are often grouped together as they share mesenchymal origin and treatment guidelines. Also, with some exceptions, a common denominator is that when the tumor cannot be cured with surgery, the efficacy of current therapies is poor and new treatment modalities are thus needed. We have studied the combination of a capsid‐modified oncolytic adenovirus CGTG‐102 (Ad5/3‐D24‐GMCSF) with doxorubicin, with or without ifosfamide, the preferred first‐line chemotherapeutic options for most types of STS. We show that CGTG‐102 and doxorubicin plus ifosfamide together are able to increase cell killing of Syrian hamster STS cells over single agents, as well as upregulate immunogenic cell death markers. When tested in vivo against established STS tumors in fully immunocompetent Syrian hamsters, the combination was highly effective. CGTG‐102 and doxorubicin (without ifosfamide) resulted in synergistic antitumor efficacy against human STS xenografts in comparison with single agent treatments. Doxorubicin increased adenoviral replication in human and hamster STS cells, potentially contributing to the observed therapeutic synergy. In conclusion, the preclinical data generated here support clinical translation of the combination of CGTG‐102 and doxorubicin, or doxorubicin plus ifosfamide, for the treatment of STS, and provide clues on the mechanisms of synergy.