Oncolytic adenovirus and doxorubicin-based chemotherapy results in synergistic antitumor activity against soft-tissue sarcoma

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. What's new? New treatment options are needed for patients with soft-tissue sarcomas (STS) as management of metastatic disease is currently not very successful. Here the authors develop a new line of treatment, where they add an oncolytic adenovirus, CGTG-102 (Ad5/3-D24-GMCSF) to doxorubicin and ifosfamide, the preferred chemotherapeutic regimen against most types of STS. They show in an immune-competent Syrian hamster model that this combination is effective against established STS tumors. In an additional line of research, doxorubicin without ifosfamide synergized with CGTG-102 to treat STS of human origin in a mouse xenograft tumor model. These results support a future clinical application of CGTG-102 in combination with doxorubicin-based chemotherapy for better treatment of STS.