Cell Landmark Study: A New Oncolytic Virus Therapy Effectively Controls Disease Progression in 90% of Advanced Cancer Cases

Cell Landmark Study: A New Oncolytic Virus Therapy Effectively Controls Disease Progression in 90% of Advanced Cancer Cases

Oncolytic viruses (OV), such as adenoviruses, Newcastle disease virus, parvoviruses, and reoviruses, are being investigated in preclinical experiments and clinical trials as a promising anti-tumor strategy.

The selective replication of oncolytic viruses in tumor cells and their oncolytic effects, as well as the immune responses activated following viral lysis, are considered the primary mechanisms by which oncolytic viruses exert their anti-tumor effects, showing great promise in the treatment of malignant tumors. However, in clinical practice, oncolytic viruses face several challenges, including safety issues with intravenous injection, insufficient immunogenicity, and antiviral immune responses.

On January 17, 2025, Professor Zhao Yongxiang, Professor Shi Wei, Professor Zhang Kun, and Professor Zhong Liping from Guangxi Medical University, among others, published a research article titled “Hyperacute rejection-engineered oncolytic virus for interventional clinical trial in refractory cancer patients” in the top international academic journal Cell.

The study developed a novel intravenously injectable oncolytic virus therapy—recombinant Newcastle disease virus carrying the pig α1, 3GT gene (NDV-GT), achieving a significant clinical breakthrough in the treatment of advanced cancer. After intravenous injection, this virus can disguise tumors to “appear” like pig organs, triggering a hyperacute rejection response and deceiving the immune system to attack these tumors, thereby inhibiting tumor growth and even completely eliminating them.

In preclinical studies, intravenously injected NDV-GT demonstrated robust tumor clearance ability in a CRISPR-mediated primary hepatocellular carcinoma monkey model. In a clinical trial involving 20 patients with recurrent/refractory metastatic cancer, the disease control rate reached as high as 90.00%, with durable responses and no severe adverse events or clinically functional neutralizing antibodies. This study highlights the great potential of genetically engineered oncolytic viruses in cancer treatment and lays the foundation for future clinical applications.

Oncolytic viruses (Oncolytic Viruses, OV) are a class of viruses that can selectively infect and kill tumor cells while activating the host's anti-tumor immune response. However, existing oncolytic viruses face several limitations in clinical applications, including:

Insufficient immunogenicity: The immune response triggered by the virus is weak, making it difficult to effectively suppress tumor growth.

Safety issues with intravenous injection: Current oncolytic viruses pose safety concerns when administered intravenously, potentially causing damage to normal tissues.

Antiviral immune response: The virus may induce neutralizing antibodies in the body, which can weaken the therapeutic effect.

To address these issues, the research team developed a genetically engineered oncolytic virus based on Newcastle Disease Virus (NDV) called NDV-GT. By integrating the porcine α1,3-galactosyltransferase gene (α1,3GT) into the NDV genome, the NDV-GT virus was constructed. This virus can express the αGal antigen in tumor cells, allowing the immune system to recognize the tumor as a foreign pig organ and trigger a hyperacute rejection response, thereby enhancing the anti-tumor immune reaction.

The research team tested the infectivity and oncolytic effects of the NDV-GT virus in various tumor cell lines (hepatocellular carcinoma, ovarian cancer, cervical cancer, etc.) and normal cell lines. Additionally, using CRISPR-Cas9 gene-editing technology, the team established a primary hepatocellular carcinoma model in cynomolgus monkeys to further validate the in vivo anti-tumor effects of NDV-GT.

These preclinical studies demonstrated the following:

Specific oncolytic effects of NDV-GT: NDV-GT exhibited specific cytotoxicity against tumor cells both in vitro and in vivo, with minimal impact on normal cells.

Hyperacute rejection response triggered by NDV-GT: Tumor cells infected with NDV-GT expressed the αGal antigen, triggering a hyperacute rejection response that led to tumor vascular thrombosis and tumor necrosis.

Enhanced immune response by NDV-GT: NDV-GT not only directly lysed tumor cells but also activated humoral and cellular immune responses, thereby enhancing the anti-tumor effect.

Based on these preclinical findings, the research team initiated a clinical trial recruiting 23 patients with refractory cancers, including hepatocellular carcinoma, ovarian cancer, cervical cancer, lung cancer, esophageal cancer, rectal cancer, breast cancer, and melanoma. These patients received intravenous injections of NDV-GT once a week for 8 to 12 weeks. Tumor shrinkage was assessed using imaging techniques such as PET-CT, CT, and MRI, and the patients' immune responses were evaluated using immunological markers.

The clinical trial results showed that NDV-GT treatment significantly enhanced the patients' immune responses, including the activation of T cells and dendritic cells, as well as the secretion of various cytokines. Among the 20 patients who completed the treatment, the disease control rate (DCR) reached 90%, with 1 complete response (CR), 6 partial responses (PR), and 11 cases of stable disease (SD). In terms of safety, NDV-GT treatment did not cause severe side effects. Although the patients' neutralizing antibody levels increased slightly, they remained within the normal range and did not affect the therapeutic efficacy.

NDV-GT effectively inhibits tumor progression in patients with various advanced cancers, without causing severe toxicity.

The study innovatively introduced the porcine α1,3GT gene, successfully triggering a hyperacute rejection response and enhancing the anti-tumor immune reaction, thereby overcoming the limitations of existing oncolytic viruses. It demonstrated good efficacy and safety in various recurrent/refractory metastatic cancers and holds broad prospects for clinical application. Additionally, the research team plans to explore the combination of NDV-GT with other immunotherapies to further improve cancer treatment outcomes.

Overall, the study successfully developed a genetically engineered oncolytic virus based on Newcastle disease virus (NDV) — NDV-GT. By triggering a hyperacute rejection response, it significantly enhanced the anti-tumor immune reaction. Preclinical and clinical trial results indicate that NDV-GT demonstrates remarkable efficacy and good safety in treating various refractory cancers, providing new ideas and technical support for the development of oncolytic virus therapies.

It is worth mentioning that the top international academic journal Nature published a news article titled “How to trick the immune system into attacking tumors,” which positively evaluated this research achievement.

Professors Zhao Yongxiang, Shi Wei, Zhang Kun, and Zhong Liping from Guangxi Medical University are the co-corresponding authors of the Cell paper. Professors Zhong Liping from Guangxi Medical University, Gan Lu, Professor Wang Bing from the Second Xiangya Hospital of Central South University, and Chief Physician Wu Tao from the First People's Hospital of Changde are the co-first authors of the paper.

https://www.cell.com/cell/fulltext/S0092-8674(24)01423-5

The H9 cells (Catalog No.: YC-C097) and stem cell culture medium (Catalog No.: YM-HA-001) used in this study were provided by Ubigene Biosciences.

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