Year: 2015
Type: dissertation
Abstract: Despite the numerous advances in cancer therapy over the past 50 years, cancer still remains the major cause of mortality worldwide, and thus new and more efficient treatments are needed. Oncolytic viruses have shown promising results in preclinical and clinical studies for the treatment of solid tumors, but their efficacy often remains low. A multitude of viral strains, such as adenovirus, have been engineered to become tumor-selective and to stimulate the immune system against the tumors. One example of oncolytic virus is Ad5/3-D24-GMCSF, a tumor-selective 5/3 chimeric oncolytic adenovirus armed with the immunostimulatory granulocyte-macrophage colony-stimulating factor (GM-CSF). In this thesis, we studied the utility of Ad5/3-D24-GMCSF in the treatment of sarcoma, melanoma and breast cancer. The virus showed strong oncolytic potential in vitro and antitumor efficacy in immunodeficient animal models. Furthermore, replication-linked GM-CSF production stimulated the differentiation of human monocytes into macrophages, important for induction of antitumor immune responses. In immunocompetent Syrian hamsters with soft-tissue sarcoma (STS) tumors, Ad5/3-D24-GMCSF reached non-injected tumors through vascular circulation, suggesting its utility for the treatment of metastatic disease. We showed that combining Ad5/3-D24-GMCSF with chemotherapeutics that possess immunogenic properties (doxorubicin and ifosfamide) and that selectively reduce circulating regulatory T-cells (cyclophosphamide), enhanced adenoviral replication and induced immunogenic cell death, setting the stage for clinical testing of combination regimens. Finally we reported safety and possible signs of efficacy in 40 patients with advanced sarcoma, melanoma and breast cancer, who were treated in the context of an Advanced Therapy Access Program (ATAP). Treatments were overall well-tolerated, and objective signs of treatment benefits were also observed. Therefore, our results confirm previous good data regarding Ad5/3-D24-GMCSF as a promising agent for treatment of cancer. Furthermore, our data may prove useful for clinical development of oncolytic adenoviruses combined with low-dose chemotherapy for the treatment of advanced sarcoma, melanoma and breast cancer, and may help to design optimal clinical trials.
Source: Työväentutkimus Vuosikirja
Author: Simona Bramante
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2228424280