Macrophage delivered oncolytic virotherapy in triple negative breast cancer

Background: Triple negative breast cancer (TNBC) is a high cause of morbidity and mortality. Novel treatments for TNBC are needed to extend the overall survival of patients with metastatic TNBC where the prognosis remains poor. A high density of tumour associated lymphocytes and macrophages in TNBC is the foundation for exploration of immunotherapy-based treatments such as oncolytic virotherapy. Oncolytic virotherapy initiates immune cell activation against cancer cells through direct cell lysis and the induction of immunogenic cell death. The overarching hypothesis of this thesis is to assess the suitability of an HSV-1 derived virus, HSV1716, in TNBC and whether the delivery of HSV1716 can be enhanced through packaging viral particles within macrophages prior to administration.

Methods: Firstly, suitable metastatic TNBC models were identified. Next, primary and metastatic immunocompetent models of TNBC were used to assess the efficacy of HSV1716 with a focus on immune cell activation. Finally, macrophage delivery oncolytic virotherapy was assessed in several metastatic immunocompetent in models.

Results: A TNBC model using the 4T1 cell line in BALB/c mice which allowed for immune cell analyses and captured the aggressiveness of TNBC was identified. HSV1716 was found to be efficacious in controlling tumour burden in primary and metastatic models and immune cell activation was confirmed. Macrophages were found to be permissive to HSV1716 and proliferating cell nuclear antigen was found to support viral replication. Macrophage delivery was found to enhance the efficacy compared to naked virus alone.

Conclusion: Oncolytic Virotherapy is a novel branch on immuno-oncology that has the potential to provide new treatment options for cancer patients. This PhD describes experiences with oncolytic virotherapy using intravenous HSV1716 in several in vivo TNBC models and forms the foundation for discussion about the feasibility of clinical trials within this area.