title: Oncolytic adenovirus and doxorubicin-based chemotherapy results in synergistic antitumor activity against soft-tissue sarcoma.
abstract: 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.
authors: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Mikko
authors: M
authors: Siurala
authors: Simona
authors: S
authors: Bramante
authors: Lotta
authors: L
authors: Vassilev
authors: Mari
authors: M
authors: Hirvinen
authors: Suvi
authors: S
authors: Parviainen
authors: Siri
authors: S
authors: Tähtinen
authors: Kilian
authors: K
authors: Guse
authors: Vincenzo
authors: V
authors: Cerullo
authors: Anna
authors: A
authors: Kanerva
authors: Anja
authors: A
authors: Kipar
authors: Markus
authors: M
authors: Vähä-Koskela
authors: Akseli
authors: A
authors: Hemminki
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003131:Combined Modality Therapy; D006224:Cricetinae; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000494:pharmacology / Q000627:therapeutic use; D007890:Leiomyosarcoma / Q000276:immunology / Q000628:therapy*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000276:immunology*; D012509:Sarcoma; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D007069:Ifosfamide
keywords: GMCSF; chemotherapy; immunogenic cell death; oncolytic adenovirus; soft-tissue sarcoma