Abstract 1786: Targeting the immunosuppressive microenvironment of metastatic breast cancer with viroimmunotherapy
Authors: Sohoni Sagar Shashikant , Nguyen Teresa , Shin Dong Ho , Fan Xuejun , Hong Jiang , Gupta Sumit , Ossimetha Ashley , Yi Yanhua , Bartholomeusz Chandra , Alonso Marta , Fueyo Juan , Gomez-Manzano Candelaria 
Published: July 2021

Metastatic breast cancer is the second leading cause of cancer related death among women. Although, conventional therapies such as surgery, adjuvant and neoadjuvant therapies have shown promising outcomes in preclinical and clinical settings, long-term survival rates remain unacceptably low for patients with recurrent disease or disseminated metastases. Breast primary and metastasic niches are characterized by an immunosuppressive microenvironment. Hence, novel therapeutic regimens that modulate this challenging phenotype are desperately needed. Our group has developed and tested in preclinical models and in clinical trials for patients with recurrent glioblastoma the anti-tumor effect of oncolytic adenovirus Delta-24-RGD, also named DNX-2401, resulting with a 20% of long-term survivors, and the awaking of a antitumoral immunity after the administration of the pathogen. This paradigm shift suggests that viroimmunotherapy can be used for the treatment of metastasic cancer. Thus, here we hypothesize that viroimmunotherapy is capable of exerting abscopal effects to eradicate primary breast tumors and their metastatic niches. To test the hypothesis, 4T1 tumor bearing mice were subjected to the local administration of Delta-24-RGD and its armed derivatives, expressing expressing immune co-stimulatory ligands OX40L (Delta-24-RGDOX or DNX-2440) and GITRL (Delta-24-GREAT). We found that, the tumors treated with oncolytic adenoviruses exhibited increase of both CD8+ T cell infiltration and CD8+/CD4+ ratio. Additionally, T-cell activity measured by IFN-γ secretion of splenocytes when in co-culture with breast cancer cells was found to be increased in mice that underwent viroimmunotherapy (P&lt;0.05, ANOVA). In addition, flow cytometry analysis of tumor-infiltrating lymphocites showed a decrease in population of exhausted T cells and MDSCs in tumor microenvironment (P&lt;0.001, ANOVA). Most importantly, animals that underwent viroimmunotherapy showed increase in overall survival (P&lt;0.005, logrank test) with decrease in number of metastatic niches in distant organs as compared to control group. In conclusion, immunological studies indicate that viroimmunotherapy enhances the infiltration and activation of T-cell specific anti-tumor response, stagnating primary tumor growth and metastasis leading ultimately to increase in overall survival. Therefore, we conclude that armed-oncolytic Delta-24-RGD based adenoviruses hold great potential in treatment of primary and metastatic breast cancer.

Citation Format: Sagar Shashikant Sohoni, Teresa Nguyen, Dong Ho Shin, Xuejun Fan, Jiang Hong, Sumit Gupta, Ashley Ossimetha, Yanhua Yi, Chandra Bartholomeusz, Marta Alonso, Juan Fueyo, Candelaria Gomez-Manzano. Targeting the immunosuppressive microenvironment of metastatic breast cancer with viroimmunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1786.