Abstract 4053: Partial reversion of the tumor immunosuppressed environment by oncolytic adenoviruses armed with positive stimulators of the immune synapsis in breast cancer
Authors: Martinez Francisco W. Puerta , Rivera Yisel A. , Nguyen Teresa , Fan Xuejun , Shifat Rehnuma , Hossain Mohammad Belayat , Jiang Hong , Bartholomeusz Chandra , Frederick Lang F. , Fueyo Juan , Gomez-Manzano Candelaria 
Published: August 2018

Immunotherapy is currently one of the primary focuses of cancer research and has the potential to become the standard treatment for oncologic patients over the next decades. Promising clinical responses have been observed in patients treated with a variety of immune-targeted therapies such as checkpoint inhibitors, modified dendritic cells, and T cell or NK cell-based immunotherapies. However, the efficacy of these treatments is still very limited due to multiple factors related to tumor nature and microenvironment. Hence, combination therapies aimed at modulating the strong tumor immunosuppressive microenvironment and stimulating T-cell infiltration into the tumor lesions are urgently needed to overcome cancer intrinsic resistance mechanisms. Preclinical and clinical studies have shown the efficacy of oncolytic virotherapy to elicit antitumor immune responses and to increase infiltration of both innate and adaptive immune cells. These capabilities of the oncolytic viruses can be enhanced and exploited to improve response of patients to different immunotherapies. Here we tested the ability of two modified oncolytic adenoviruses termed Delta-24-RGDOX and Delta-24-GREAT, expressing OX40L and GITRL respectively, to modify the tumor microenvironment in different murine triple-negative breast cancer models. We hypothesized that intratumoral injection of these armed oncolytic adenoviruses will decrease immunosuppression within the tumor microenvironment. To this end, mice harboring fat pad tumors were treated with intratumoral doses of these armed oncolytic adenoviruses. Leukocytes from spleen and tumor tissues were analyzed for the relative presence of lymphocyte and myeloid cell subsets. In all mice treated with Delta-24-RGDOX or Delta-24-GITRL, CD8+ T-cell populations were significantly higher compared with those observed in the control mice. Significantly lower percentages of cell populations with immunosuppressive phenotypes, such as PD-1+ T cells (P&lt;0.0001, Student t-test), CD4+CD25+ Foxp3+ regulatory T cells (P&lt;0.0001, Student t-test) and MDSC (P&lt;0.0001, Student t-test) were found in the mice treated with the armed oncolytic adenoviruses. Taken together, our results confirmed the strong immunomodulatory effect of enhanced oncolytic viruses, which can be easily combined with immune-modulating checkpoints, for the treatment of deadliest human cancers.

Citation Format: Francisco W. Puerta Martinez, Yisel A. Rivera, Teresa Nguyen, Xuejun Fan, Rehnuma Shifat, Mohammad Belayat Hossain, Hong Jiang, Chandra Bartholomeusz, Lang F. Frederick, Juan Fueyo, Candelaria Gomez-Manzano. Partial reversion of the tumor immunosuppressed environment by oncolytic adenoviruses armed with positive stimulators of the immune synapsis in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4053.