Dual-action virus targets both cancer cells and associated fibroblasts

Carcinoma-killing virus enadenotucirev is being used to specifically deliver a T-cell engaging protein that targets tumor-associated cells, whilst having no effect on normal, unassociated cells in the rest of the body.

Cancer-associated fibroblasts are healthy cells that are tricked by their neighboring cancerous cells to provide tumors with growth factors and nutrients, and to protect them from the immune system. For the first time, researchers have specifically targeted these cells, by equipping a virus with a bispecific protein. Current methods of targeting these fibroblasts cannot differentiate between ‘helper’ fibroblasts and unrelated fibroblasts in other areas of the body, causing toxicity and unwanted side effects.

In this new study, primarily funded by the Medical Research Council and Cancer Research UK, researchers added genetic instructions to enadenotucirev, causing the infected tumor cells to produce a bispecific T-cell engager protein, a cellular action otherwise suppressed by cancer.

First author Joshua Freedman (Department of Oncology, University of Oxford, UK) explained: “We hijacked the virus’s machinery so the T-cell engager would be made only in infected cancer cells and nowhere else in the body. The T-cell-engager molecule is so powerful that it can activate immune cells inside the tumor, which are being suppressed by the cancer, to attack the fibroblasts.”

The T-cell engager protein binds to both fibroblasts and T-cells, triggering the T-cells to kill the bound fibroblasts. As the virus only infects cancerous cells, healthy cells remain unaffected.

“Even when most of the cancer cells in a carcinoma are killed, fibroblasts can protect the residual cancer cells and help them to recover and flourish. Until now, there has not been any way to kill both cancer cells and the fibroblasts protecting them at the same time, without harming the rest of the body,” commented Kerry Fisher (Department of Oncology, Oxford University).

“Our new technique to simultaneously target the fibroblasts while killing cancer cells with the virus could be an important step towards reducing immune system suppression within carcinomas and should kick-start the normal immune process.”

The research team tested the virus on human cancer samples, including prostate cancer tumors, and on samples of healthy bone marrow. They found that, whilst the virus attacked the cancer cells and the surrounding fibroblasts, it did not cause toxicity in the healthy samples.

Michelle Lockley, Cancer Research UK’s immunotherapy expert, concluded: “This work in human tumor samples is encouraging, but can be complicated – one of the biggest challenges of immunotherapies is predicting how well they will work with the patient’s immune system, and understanding what the side effects could be. The next stage will be using clinical trials to test whether this is both a safe and effective way to treat the disease in people.”

The scientists hope that the virus could enter clinical trials as early as next year, and look forward to further study on the use of immunotherapy in the treatment of cancers.

Source: Freedman J et al. Simultaneously targeting cancer and immunosuppressive stromal cells using an oncolytic virus expressing a T-cell engager. Cancer Res. (2018).