In Vitro and In Vivo Efficacy of a Stroma-Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer

• Published in: International journal of molecular sciences Vol. 24; no. 12; p. 9992
• Main Authors: Alfano, Ana, Cafferata, Eduardo G A, Gangemi, Mariela, Nicola Candia, Alejandro, Malnero, Cristian M, Bermudez, Ismael, Lopez, Mauricio Vargas, Ríos, Gregorio David, Rotondaro, Cecilia, Cuneo, Nicasio, Curiel, David T, Podhajcer, Osvaldo L, Lopez, Maria Veronica
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-06-2023; MDPI
• Subjects: Adenoviridae - genetics; Adenoviridae Infections; adenovirus; Adenoviruses; Analysis; Animals; Ascites; Cancer; Cancer therapies; Cell Line, Tumor; Cervical cancer; Cervix; Chemotherapy; Cisplatin; cytokines; Explants; Female; gene therapy; gynecologic neoplasms; Gynecology; Humans; Hypoxia; Mice; Mice, Nude; Mortality; Oncology, Experimental; Oncolysis; Oncolytic Virotherapy; Oncolytic Viruses - genetics; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - therapy; Stroma; Telomerase reverse transcriptase; Tumor Microenvironment; Tumors; Uterine cancer; Uterine Cervical Neoplasms; Uterus; Womens health; Xenograft Model Antitumor Assays; gene therapy; gynecologic neoplasms; cytokines; ovarian cancer; adenovirus
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24129992

More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV), whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer, uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404), a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.