Metastasis of advanced stage cancers remains as the main cause of morbidity and mortality in oncologic patients. Metastatic cancers, especially those that metastasize to the brain, are generally resistant to conventional therapies. Thus, more innovative and efficacious therapies are urgently needed. Therapeutic goals are the specific targeting of malignant cells, shrinkage of stablished tumors, prevention and/or eradication of metastases and, ultimately, induction of a specific anti-tumor immune response. In this study we tested the efficiency of a treatment regimen consisting of oncolytic adenoviruses combined with specific immune regulators to prevent tumor progression and metastasis. In order to do so, mouse metastatic breast cancer cells 4T1 or 66c14, were orthotopically implanted in female BALB/c mice. The resulting primary tumors were treated with multiple doses of third generation adenoviruses targeting different immune checkpoints, such as, OX40/OX40L and GITR/GITRL pathways in the immune synapse. The treatment with these adenoviral constructs resulted in T cells activation and reduction of the metastases in 50% of the mice. In addition, the size and number of the metastases detected in lungs were significantly lower comparing with those observed in the control groups. Survival rates were also significantly different (P < 0.046) when compared to controls. FACS analysis of isolated tumor-infiltrating lymphocytes, as well as, splenocytes showed that OX40/OX40L or GITR/GITRL immune therapies were able to activate and increase the number of cytotoxic T cells and suppress tumor anergy. In summary, we demonstrated for the first time that Delta-24-RGDOX and Delta-24-GREAT, expressing OX40L and GITRL respectively, display antitumor effect on immune competent models of metastatic breast cancer.

Citation Format: Francisco W. Puerta Martinez, Yisel A. Rivera, Teresa Nguyen, Xuejun Fan, Jared M. Henderson, Shifat Rehnuma, Mohammad B. Hossain, Hong Jiang, Juan Fueyo, Candelaria Gomez Manzano. Oncolytic adenoviruses expressing OX40L or GITRL immune modulators show antitumor effect on immune-competent mouse breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3668. doi:10.1158/1538-7445.AM2017-3668