Project 458550

Breast cancer is the most common cancer affecting women worldwide. Triple negative breast cancer (TNBC) accounts for 12-15% of cases, and is the most aggressive form of breast cancer with the highest ability to spread. Currently, there are no approved targeted therapies available, leaving patients with limited therapeutic options. Cancer immunotherapies harness a patient's immune system to fight their own cancer. Natural Killer (NK) cells are immune cells which recognize and directly kill tumor cells while leaving healthy cells unharmed. NK cell activation can be further enhanced by expression of chimeric antigen receptors (CARs) which bind to proteins expressed on the surface of tumor cells. CAR-modified NK cells have shown impressive anti-cancer efficacy against blood cancers and importantly, do not result in any unwanted side effects. Recently, using immune cells expressing CARs against the EGFR protein has shown promise for treating TNBC. However, despite their promising anti-cancer potential, NK cell treatment has been less beneficial against solid tumors like breast cancer. Our research findings show that NK cells are unable to fully eliminate established TNBC tumors in mice because they cannot travel to and enter into the tumor mass. Thus, developing novel ways to improve NK cell trafficking into the solid tumor is necessary to fully maximize their anti-tumor response. To overcome this problem, we will harness the anti-tumor properties of oncolytic viruses (OVs). OVs directly infect tumor cells without targeting healthy cells and induce immune responses against the tumor. We will specifically use Orf virus, which has been shown to effectively target lung cancer and TNBC through the recruitment and activation of NK cells. We believe that combining Orf virus with EGFR specific CAR-NK cells will facilitate NK cell infiltration into the solid tumor, extending this type of therapy against breast cancer and other solid cancers currently lacking treatments.