The oncolytic virus of p53-armed NDV, in combination with GM-CSF and iPD-L1, induces the Immunogenic cell death of melanoma

Abstract

Melanoma is a malignant tumor that mutates from melanocytes on the skin and mucous membranes. (Long et al., 2023) Cutaneous melanoma is the most dangerous skin cancer, which causes 80% of causalities (Saeed et al., 2024). The treatment of melanoma includes wide excision and radiotherapy, which makes it hard to perform a systematic impact and could produce side effects (Sakunchotpanit et al.,2024). As immunotherapy, oncolytic virus therapy provides a pathway to combine a direct attack of this cancer, leading to a favorable prognosis. However, oncolytic virus therapy is fraught with challenges as the generally immunosuppressive tumor microenvironment interferes with inducing an effective systemic immune response. To overcome the immunosuppression, activate the innate immune response, and cause an abscopal effect in tumor treatment, we propose building on a previously described recombinant Newcastle disease virus (NDV) encoding GM-CSF, MEDI5395. Oncolytic virotherapy induces immunogenic cell death (ICD) and antitumor immune responses, which can cause the abscopal effect simultaneously. It has previously been shown that p53 expression in OVs can induce more severe ICD and enhance T-cell infiltration, leading to reduced tumor growth and long-lasting systemic anti-tumor immune response in preclinical models by secreting adenosine triphosphate (ATP) and high-mobility group box protein B1(HMGB1). In this way, untreated tumor cells are also suppressed. iPD-L1 combined with GM-CSF effectively reduces tumor viability, enhances immune cell infiltration, and upregulates immune-related genes, promoting systemic anti-tumor immunity and improved survival in mouse melanoma models. We hypothesize that NDV encoding p53 and iPD-L1/GM-CSF effectively induce immunogenic cell death, enhance immune cell infiltration, and reduce tumor growth, demonstrating significant therapeutic potential in preclinical models. In conclusion, editing such genes in NDV can potentially enhance melanoma’s treatment efficacy, resulting in systemic anti-tumor responses.