Oncolytic viruses as an antitumor therapy
Certain viruses, such as adenovirus, Newcastle disease virus NDV, parvovirus, and reovirus, can selectively lyse tumor cells and trigger immune responses, making them promising agents for cancer treatment. However, their clinical efficacy remains limited due to insufficient viral replication in tumors, weak immune stimulation, and an immunosuppressive tumor microenvironment.
Genetically engineered oncolytic viruses
To enhance the antitumor potential of oncolytic viruses, researchers have developed genetically modified variants capable of targeting both primary and metastatic tumors. Some oncolytic viruses have reached clinical trials, particularly in combination with immunotherapy. However, the clinical outcomes have not met expectations, as the immune response in real-world conditions is often weaker than in laboratory settings.
Key challenges in the clinical application of oncolytic viruses
- Insufficient infection efficiency and replication in tumor cells in vivo.
- Unverified safety of intravenous administration. During rapid division and replication, genetic modifications are likely lost, which could restore the virus’s ability to infect and damage normal cells. To mitigate this risk, oncolytic viruses are often administered locally into tumors rather than intravenously, significantly reducing their effectiveness.
- The host immune response to the virus is often too weak to overcome the tumor’s immunosuppressive environment.
- The host typically develops high-titer neutralizing antibodies against oncolytic viruses, preventing repeated administration and significantly reducing therapeutic efficacy.
Development of an oncolytic Newcastle disease virus
Researchers at Guangxi Medical University in China have engineered a modified NDV strain that effectively lyses tumor cells while exhibiting low immunogenicity. Unlike many other viruses, NDV does not replicate in normal cells and does not cause damage to healthy tissues, even if it reverts to its wild-type form.
Recombinant NDV-GT carrying the α1,3GT gene
The researchers utilized NDV as a vector to deliver the α1,3GT gene, designed to amplify oncolytic effects. The resulting NDV-GT virus induces tumor cells to express αGal or alpha-galactosidase.
αGal is a foreign antigen that triggers a hyperacute rejection response against xenografts. This reaction is characterized by thrombosis due to damage to donor endothelial cells, leading to the release of platelet-activating factor PAF. For example, such a response occurs within minutes or hours after porcine heart transplants are connected to the human circulatory system. The reason is natural anti-αGal antibodies in humans, which facilitate the destruction of endothelial cells in xenografts. The damaged endothelial cells release PAF, causing thrombosis and loss of graft function.
NDV-GT for cancer therapy
The gut microbiota produces anti-αGal antibodies, making the hyperacute rejection response applicable to cancer therapy. NDV-GT forces tumor cells to express αGal, triggering a potent immune response, weakening the tumor’s immunosuppressive microenvironment, and promoting tumor destruction. The study demonstrated the efficacy of NDV-GT against various cancers, including liver, ovarian, colorectal, lung, breast, esophageal, melanoma, and cervical cancers.
NDV-GT holds significant clinical potential for late-stage cancer patients, as it selectively infects only tumor cells. In cell culture experiments, αGal expression enhanced NDV’s oncolytic activity, eliminating 90% of human hepatocellular carcinoma cells within 72 hours.
In macaque studies, tumors in the NDV-GT group were significantly smaller after three months of treatment than in the NDV-only group and the PBS phosphate-buffered saline group. In the NDV-GT group, tumors completely regressed within three months after treatment cessation, and all macaques survived. In contrast, tumors in the NDV-only group initially shrank but rapidly regrew after treatment cessation, leading to the death of two macaques within three months. The PBS group showed a maximum survival of five months, with an average survival of just over four months.
In the NDV-GT group, αGal expression was limited to tumor tissues and absent from adjacent healthy tissues. Thrombosis was observed within the tumor vasculature following NDV-GT treatment, leading to vascular occlusion. These findings suggest that NDV-GT efficiently induces αGal expression, making tumors a target for natural anti-αGal antibodies in the bloodstream. The formation of intratumoral thrombi ultimately led to tumor shrinkage and necrosis. Hyperacute rejection also triggered a robust activation of both humoral and cellular immune responses, ultimately leading to complete tumor regression.
Mechanism of action of NDV-GT
NDV-GT infection induces αGal expression in tumor cells, which then bind to natural anti-αGal antibodies, initiating tumor cell destruction. Additionally, NDV-GT directly lyses tumor cells. This process releases αGal and tumor antigens, activating the adaptive immune response via antigen-presenting cells.
Inflammatory factors and chemokines within the tumor microenvironment facilitate T-cell migration and infiltration, underscoring the importance of CD4 and CD8 T-cell activation for successful immunotherapy. αGal promotes T-cell differentiation, proliferation, and activation, leading to secretion of interferon-gamma IFN-γ and tumor necrosis factor-alpha TNF-α by CD4 and CD8 T-cells.
Thus, NDV-GT exerts a direct oncolytic effect and induces high αGal expression, triggering hyperacute rejection and initiating immune responses that suppress tumor growth.
Safety assessment of NDV-GT in macaques
Intravenous administration of NDV-GT once weekly for 12 weeks had no significant impact on body weight, temperature, heart rate, physiological parameters, coagulation factors, liver and kidney function, or blood glucose levels. There were no observed changes in urine protein, leukocytes, or occult blood in feces, and no noticeable damage to normal organs.
Neutralizing antibody titers against NDV were measured before treatment and at various intervals throughout the study. A slight increase in neutralizing antibodies was observed, but titers remained within the normal control range, and this increase was not clinically significant. The development of neutralizing antibodies did not impair the therapeutic efficacy of NDV-GT.
Clinical application of NDV-GT in cancer patients
A study involving 23 patients with treatment-resistant cancers, including liver, ovarian, cervical, lung, esophageal, colorectal, breast, and melanoma, showed a disease control rate of 90% with minimal toxicity.
A patient with primary hepatocellular carcinoma and lung metastases experienced tumor shrinkage and even complete disappearance after 1.5 months of NDV-GT treatment. The patient remained stable for 10 months.
Image source: https://www.cell.com/cell/fulltext/S0092-8674(24)01423-5
The treatment suppressed tumor progression, significantly reducing the level of the liver cancer biomarker AFP (alpha-fetoprotein). Immunological analysis post-treatment demonstrated that NDV-GT stimulates adaptive immunity, reactivates the immune memory system, mitigates immunosuppression, activates natural antitumor immunity, and functions as both humoral and cellular immunotherapy. The therapy promoted the secretion of antitumor cytokines without inducing cytokine release syndrome (CRS). NDV-GT treatment was safe, showing no adverse effects on blood parameters or kidney function except for a slight increase in inflammation.
The titer of neutralizing antibodies against NDV post-treatment was slightly higher than pre-treatment levels but remained within the normal control range, which indicates that the immune system did not eliminate the virus, allowing for potential re-administration. The treatment activated cytokines that stimulate the JAK-STAT signaling pathway, which regulates interactions between viral proteins and cytokines or cytokine receptors.
In another patient with extensive peritoneal metastases originating from ovarian cancer, treatment induced significant infiltration of T lymphocytes into the tumor tissue, leading to an escalating oncolytic response. The ovarian tumor initially shrank and then completely disappeared.
Another patient was diagnosed with progressive cervical cancer with metastases to the iliac crest, causing extensive bone destruction in the sacrum, iliac bones, and acetabulum. This patient had previously undergone radiation and chemotherapy. The bone metastases disappeared after three months of combined intravenous and peritoneal injections of NDV-GT over six months. The patient experienced a significant reduction in bone pain, eliminating the need for analgesics. The tumor did not progress; however, the patient succumbed to septic shock after 36 months.
In another patient with a similar clinical presentation, NDV-GT treatment over three months significantly reduced or eliminated metastatic bone and pelvic lymph node lesions. The patient experienced a marked reduction in bone pain, allowing for the discontinuing of analgesics. After 36 months, the patient remained stable and still alive.
Environmental safety of NDV-GT
PCR tests conducted seven days post-injection confirmed the presence of the virus in patients’ blood but indicated that NDV-GT did not spread to the environment, demonstrating its biosafety.
Nevertheless, individuals working with or owning birds should avoid contact with them post-injection to minimize potential risks to susceptible species.
Useful article, necessary information? Share it!
Someone will also find it useful and necessary:
