Engineered Stem Cells Releasing Oncolytic Virus and Immunomodulators Have Therapeutic Efficacy in Brain Metastatic Tumors

Abstract

Background: Brain metastasis is common among patients with advanced lung cancer and melanoma and is associated with significant morbidity and mortality. Conventional treatments, such as surgery, radiation, and chemotherapy, have shown limited effectiveness in improving patient outcomes, highlighting the need for novel treatment options. Importance: Co-delivering oHSV releasing stem cells and oHSV resistant stem cells releasing immunomodulators may provide better therapeutic outcomes in brain metastasis (BM) mouse tumors. Materials and Methods: We evaluated the mechanism of action in a co-delivery system based on mesenchymal stem cell (MSC) and oncolytic herpes virus (oHSV) in metastatic mouse tumors. We used viral entry receptor Nectin-1 knock out MSC (MSCN1KO) to release immunomodulators, single chain antibody against PD-1 (scFvPD-1)or scFvPD-1 and Granulocyte macrophage colony stimulating factor (GM-CSF) (MSCN1KO -G/P). To increase oHSV mediated oncolysis, we also created Nectin-1 receptor overexpressing MSCs (MSCN1) and investigated therapeutic efficacy with MSCN1-oHSV and MSCN1KO-scFvPD1. Results: We show that MSCN1KO- scFv-PD-1 or G/P in combination with MSC-oHSV have sustained co-delivery and better therapeutic efficacy in brain metastasis mouse tumors. We demonstrated a significant increase of viral titration in MSCN1 compared to control MSC which results in reduction of tumor volumes in brain metastatic tumors. Finally, we show that mice bearing brain metastatic tumors treated with MSCN1-oHSV and MSCN1KO -scFvPD-1 had considerably longer overall survival than those treated with either MSCN1-oHSV or MSCN1KO-scFvPD-1 alone. Conclusion: This study demonstrates that genetically modified MSCs (Nectin-1 on/off) can be used to deliver oHSV and immunomodulators for the treatment of metastatic brain tumors.