Pancreatic Cancer
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Researchers from Queen Mary University of London and Zhengzhou University have developed what they claim is a powerful therapeutic platform that harnesses a modified Vaccinia virus (VV) for treating pancreatic cancer (PaCa). The newly reported studies showed that use of the oncolytic virus (OV) in combination with other drugs significantly extended survival in preclinical models of pancreatic cancer. The team hopes that clinical trials may start within a few years.

Commenting on the new treatment approach, Louisa Chard Dunmall, PhD, 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 [Medical Research Council] to support this project through preclinical 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.”

Dunmall is joint first author of the researchers’ published paper in the Journal for ImmunoTherapy of Cancer, which is titled, “A systematically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer.”

Cancer is a growing global burden, the authors wrote, with the incidence expected to increase by 62% worldwide by 2040. However, existing therapies are limited by “poor efficacy and intolerable side effects.” Pancreatic cancer is the seventh leading cause of cancer death worldwide, with more than 450,000 new cases and 432,000 deaths reported in 2018. Pancreatic cancer also has the lowest survival rate of all the common cancers, with less than 7% of patients surviving for five years or more. The disease is often diagnosed when it is advanced or has metastasized, making treatment difficult.

Chemotherapy and radiotherapy alone are relatively unsuccessful in treating pancreatic cancer and while surgery to remove the tumor offers the best chance of survival, more than 80% of patients ultimately die of the disease due to local recurrence and/or distant metastasis. Moreover, the team noted, although immunotherapeutics such as immune checkpoint inhibitors (ICI) have emerged as a promising new therapeutic approach, pancreatic cancer is, in particular, unresponsive to ICI monotherapy. “While immunotherapeutics such as immune checkpoint inhibition (ICI) have emerged as a promising new approach for cancer treatment, PaCa in particular is unresponsive to ICI monotherapy,” the team stated.

Oncolytic viruses (OVs) are engineered viruses that can selectively infect and destroy cancer cells and elicit strong anti-tumor immune responses. While a promising new class of therapeutics, current oncolytic virotherapy is unable to produce a long-term cure in patients, and the treatment has to be delivered directly into the tumor—a route that is not feasible for deeply embedded tumors, or tumors that have spread around the body.

The new approach to pancreatic cancer therapy developed by the researchers in the U.K. and China, employs an oncolytic Vaccinia virus that has been modified to improve its safety, ability to spread within and between tumors and capacity to activate potent anti-tumor immune responses, and demonstrated a promising synergistic anti-tumor effect in combination with ICI immunotherapy.

The study built upon previous work by the team, which developed a modified Vaccinia virus through the deletion of two viral genes. By combining treatment using the modified virus and a clinically available PI3Kδ inhibitor that prevented the destruction of the virus particles by the body’s immune cells, the team created an effective systemic treatment platform that specifically targeted pancreatic tumors and activated the immune system against the tumors in preclinical models.

We recently described a novel thymidine kinase (TK)-deleted, N1L gene-deleted VV, VVLΔ TKΔ N1L, which demonstrated potent gene-deletion-driven tumor specificity, activation of antitumor immunity and potent efficacy in a number of tumor models in vivo,” the authors explained. Additionally, we have developed a platform to improve intravenous delivery of VV based on transient pharmacological inhibition of PI3 Kinase δ (PI3Kδ) to prevent uptake of the virus by macrophages, a major factor limiting systemic administration.”

For their newly reported study, and to improve efficacy of the treatment platform, the team re-engineered the virus by modifying its genetic code to produce an additional, altered copy of a protein that is crucial to the ability of the virus to spread within and between tumors. The team also equipped the virus with IL-21, which improved the virus’ ability to trigger an immune response against the cancer. “We armed this virus with interleukin-21 (IL-21) to improve the induction of antitumor immune responses to create VVLΔTK-STCΔN1L-IL21 (referred to hereafter as VVL-21).”

Studies showed that administration of this novel VVL-21 Vaccinia virus in preclinical models of pancreatic cancer effectively remodeled the suppressive tumor microenvironment (TME) to trigger potent anti-tumor immune responses. “In addition to enhancing innate antitumor immune responses, VVL-21 also enhanced adaptive T cell immunity, with virus treatment consistently elevating both systemic and intratumoral effector and memory T cell populations and IL-21 exacerbating the effects on effector CD8+ T cell populations further,” they noted.

Importantly, treatment with VVL-21 also sensitized tumors to immune checkpoint inhibitor therapy. The team’s experiments confirmed that combination of the three therapeutics – VVL-21, PI3Kδ inhibitor and the immune checkpoint inhibitor – created a powerful systemic therapeutic platform that significantly extended survival in a number of different, complex preclinical models of pancreatic cancer. “Intravenously administered VVL-21 successfully remodeled the suppressive tumor-microenvironment to promote antitumor immune

responses and improve long-term survival in animal models of pancreatic cancer,” they concluded. “Importantly, treatment with VVL-21 sensitized tumors to the immune checkpoint inhibitor α-PD1. Combination of PI3Kδ inhibition, VVL-21 and α-PD1 creates an effective platform for treatment of pancreatic cancer.”

Study lead Yaohe Wang, PhD, from Barts Cancer Institute, Queen Mary University of London, 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.”

Following additional funding from the MRC, the team is now hoping to conduct the necessary steps required to take the viral treatment system forward into phase I clinical trials to determine its potential within the clinic. As the authors concluded, “Together, these results describe a rationally constructed OV-based therapeutic platform that effectively addresses many of the shortfalls of current OV-based platforms in clinical development and may expand the therapeutic landscape for ICI treatments.

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