NDV-GT wth hyperacute rejection in cancer therapy

Area of Science:

• Oncolytic virotherapy
• Cancer immunotherapy
• Immunology

Background:

• Oncolytic viruses (OVs) show promise for cancer treatment but face challenges with toxicity and immunogenicity.
• Developing OVs with enhanced safety and efficacy is crucial for clinical translation.

Purpose of the Study:

• To develop and evaluate NDV-GT, a genetically engineered Newcastle disease virus (NDV) expressing porcine α-1,3-galactosyltransferase, as a novel oncolytic agent.
• To assess the immunogenicity, tumor microenvironment modulation, and clinical efficacy of NDV-GT.

Main Methods:

• Genetic engineering of NDV to express porcine α-1,3-galactosyltransferase, creating NDV-GT.
• In vitro assessment of immune responses, including complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).
• Evaluation of tumor microenvironment modulation, signaling pathway inhibition (PI3K/AKT, NF-κB), and apoptosis induction.
• Preliminary clinical study in patients with advanced refractory carcinomas.

Main Results:

• NDV-GT triggered hyperacute rejection via pre-existing natural antibodies, leading to CDC and ADCC.
• The virus converted "cold" tumors to "hot" by increasing T-cell infiltration and cytokine secretion.
• NDV-GT inhibited PI3K/AKT and NF-κB pathways, suppressing tumor proliferation and inducing apoptosis.
• In a clinical study, NDV-GT achieved a 90.0% disease control rate in 20 patients with no serious adverse events.

Conclusions:

• NDV-GT is a safe and effective oncolytic virus that elicits robust antitumor immunity.
• The engineered virus demonstrates potential for treating advanced refractory carcinomas by modulating the tumor microenvironment and inducing tumor cell death.
• NDV-GT represents a promising novel immunotherapy for cancer treatment.