The study conducted by researchers from Queen Mary University of London and Zhengzhou University is published in the Journal for Immunotherapy of Cancer.
‘For pancreatic cancer treatment, a new powerful therapeutic platform has been developed that uses a modified oncolytic Vaccinia virus called VVL-21 combined with immune checkpoint inhibitors and PI3Kδ inhibitor to trigger an anti-tumor immune response and extend survival.’
Worldwide, pancreatic cancer is the 10th most common cancer, but it is responsible for 8 percent of all cancer related deaths. It has the lowest 5-year survival among all the common cancers.
The treatment of pancreatic cancer difficult as it is mostly diagnosed in the late stages of its development when the cancer is advanced or has spread to other parts of the body.
More than 80 percent of the patients die of the disease due to local recurrence and/or distant metastasis. While surgery to remove the tumor offers the best chance of survival, chemotherapy, and radiotherapy alone are relatively not successful in treating pancreatic cancer.
What Are Oncolytic Viruses?
Oncolytic virusesare a form of immunotherapy that uses viruses to selectively infect and destroy cancer cells. Oncolytic viruses kill cancer cells and elicit a strong anti-tumor immune response by various mechanisms. They are a new promising class for cancer therapy because of several reasons like
- Cancer cells are susceptible to infections due to their impaired antiviral defenses
- The natural viruses are modified, giving them certain advantages like decreasing their ability to infect healthy cells and targeting specific tumors, and produce immune-boosting molecules after infection
- After infection of cancer cells with oncolytic viruses, the cancer cells are killed, and antigens are released that stimulate the immune response, thereby killing the remaining tumor cells
The first FDA approved oncolytic virus therapy- T-VEC (Imlygic®) is for the treatment of melanoma. T-VEC is a modified herpes simplex virus (HSV).
Currently, oncolytic virus therapy is not able to produce a long-term effect in patients. Moreover, the treatment has to be delivered directly into the tumor, which is not possible for deeply embedded tumors and those tumors spread in the body.
The researchers have come up with a novel platform for pancreatic cancer treatment using an Oncolytic Vaccinia virus, which was modified to improve its safety, its ability to spread within and between tumors, and its capacity to activate potent anti-tumor immune responses.
Modifying the Virus System
Previously, a study was conducted by a team that developed a modified Vaccinia virus by deleting two viral genes. They used a combination treatment of the modified virus and a clinically available drug called PI3Kδ inhibitor, which prevented the destruction of the virus particles by the body’s immune cells.
In preclinical models, the team successfully created an effective treatment platform that could travel through the body and specifically target pancreatic tumors and activate the immune system against these tumors.
In the new study, the efficacy of the treatment was improved by modifying its genetic code to contain an additional, altered copy of a protein, which is crucial for the ability of the virus to spread within and between tumors. To improve the virus’ ability to trigger an immune response against the cancer, the virus was armed with a protein called IL-21.
Professor Yaohe Wang, from Barts Cancer Institute, Queen Mary University of London, who led the study, said, “This platform provides a powerful therapeutic to target multiple aspects of pancreatic cancer simultaneously through a convenient administration approach (intravenous injection), significantly improving the prospects of disease eradication and prevention of recurrence in pancreatic cancer patients. This platform is also suitable for treatment of other human tumor types.”
Pre-Clinical Models Of Pancreatic Cancer
In the preclinical models of pancreatic cancer, the administration of the novel oncolytic Vaccinia virus called VVL-21 resulted in the virus successfully remodeling the suppressive tumor microenvironment to trigger a potent anti-tumor immune response. VVL-21 also sensitized the tumors to treatment with a type of immunotherapy known as an immune checkpoint inhibitor.
The combination therapy of VVL-21, PI3Kδ inhibitor, and immune checkpoint inhibitor created a powerful systemic therapeutic approach that significantly extended survival in preclinical models of pancreatic cancer.
Even though immunotherapies such as immune checkpoint inhibition (ICI) have emerged as a promising new therapeutic approach, pancreatic cancer is not responsive to ICI alone. In combination with ICI immunotherapy, the new virus treatment showed a synergistic anti-tumor effect.
To determine viral treatment system’s potential, theteam is now hoping to conduct phase I clinical trials with additional funding from MRC.
Joint first author of the study, Dr Louisa Chard Dunmall, senior postdoctoral researcher at Barts Cancer Institute, Queen Mary University of London said, “The current prognosis for patients with pancreatic cancer has not improved for many decades and so we urgently require new treatments that can improve long-term survival. Our platform provides an exciting new mechanism of attacking the tumor in these patients and we are grateful that we have received further funding from the MRC to support this project through pre-clinical toxicity testing and virus manufacture in the hope that we can take this platform forward into phase I clinical trials within the next 3 years.”
- A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer. Giulia Marelli, Louisa S Chard Dunmall, Ming Yuan, Carmela Di Gioia, Jinxin Miao, Zhenguo Cheng, Zhongxian Zhang, Peng Liu, Jahangir Ahmed, Rathi Gangeswaran, Nicholas Lemoine, Yaohe Wang. Journal for ImmunoTherapy of Cancer. doi:10.1136/jitc-2020-001624.
- How Oncolytic Virus Therapy is Changing Cancer Treatment – (https://www.cancerresearch.org/immunotherapy/treatment-types/oncolytic-virus-therapy)