Enhanced Viro-Immunotherapy for Breast Cancer Brain Metastasis

PROJECT SUMMARY/ABSTRACT Breast cancer brain metastasis (BCBM) is a major clinical challenge due to their poor response to therapeutic options. Although the survival rate of breast cancer (BC) patients has improved, the incidence of BCBM is increasing with recent advance in diagnostic imaging and systemic therapy, and long-term survival rates for

these patients are unacceptably low, urgently calling for new interventions. Oncolytic herpes simplex virus-1 (oHSV) therapy is the most advanced virotherapy as approved by FDA for melanoma in the U.S. and conditionally for glioblastoma in Japan. However, accumulating clinical data is revealing that oHSV treatment

very weakly induces a systemic anti-tumor immune response which is often offset by the immunosuppressive tumor microenvironment (TME). Thus, mechanistic identification of the anti-viral resistance is a key to maximize its therapeutic efficacy. In BCBM, we observed that oHSV therapy induces insulin-like growth factor 2 (IGF2)

expression and secretion, sustaining pro-inflammatory neutrophils in the TME and polarization change to pro- tumoral neutrophils, hampering the virus propagation and discouraging the development of a strong adaptive anti-tumoral immune response. Additionally, we found that infiltrated neutrophils by oHSV therapy induces

neutrophil extracellular trap (NET) formation (also called “NETosis”), hampering the therapeutic efficiency of Viro-Immunotherapy. The overarching goal of this application is to identify the ultimate cause of the poor clinical response of cancer patients to oHSV therapy, and develop a more effective novel viral immunotherapy for

incurable BCBM. We aim to achieve our goal by deciphering anti-viral resistance mechanism behind oHSV- induced IGF2/microglia/neutrophil axis, and evaluating therapeutic benefit of IGF2 inhibition and NET degradation on oHSV therapy. To compromise oHSV-induced IGF2 and its signaling pathways, we generated a

novel IGF2-scavanging oHSV (oHSV-D11mt) and will investigate the therapeutic benefit when combined with radiation therapy, which has also been hindered by IGF2, neutrophil infiltration and NETosis. We also generated actin resistant DNase1-expressing oHSV (oHSV-haDNase1) to degrade the NETs for enhanced virus

propagation and access to infiltrating cytotoxic lymphocytes. To test these hypotheses, we will investigate the contradictory roles of IGF2 in virus clearance and tumor progression (Aim 1), evaluate therapeutic potential of IGF2-scavenging oHSV-D11mt in combination with radiotherapy (Aim 2), and assess the preclinical efficacy of

NET-mitigating oHSV-haDNase1 (Aim 3). The successful completion of this proposed study is expected to unveil the role of neutrophil infiltration and NET formation induced by oHSV therapy, and elucidate why oHSV therapy was not as successful as viral immunotherapy as expected. Therefore, it will accelerate the translation of oHSV

therapy into an efficient and improved treatment modality for the patients with BCBM.