Modified herpes virus 'could combat skin cancer'

“Patients with aggressive skin cancer have been treated successfully using a drug based on the herpes virus,” The Guardian reports. A new study suggests a novel form of immunotherapy could be effective for treating some cases of advanced skin cancer.

This was a large trial examining the use of a new immune treatment called talimgogene laherparepvec (T-VEC) for advanced melanoma (the most serious type of skin cancer) that could not be removed surgically.

T-VEC is a modified derivative of the herpes virus that causes cold sores. It is injected directly into the tumour and causes the production of a chemical called granulocyte-macrophage colony-stimulating factor (GM-CSF), which stimulates an immune response to fight the cancer.

T-VEC injections were compared with injections of GM-CSF only, which is sometimes used to treat people who have poor immunity caused by cancer treatment. 

The trial found, overall, significantly more people responded to treatment for more than six months with T-VEC (16.3%) than with GM-CSF injections (2.1%).

It also improved overall survival, but this only just reached statistical significance, meaning we can have less confidence in this effect. Average survival was 23.3 months with T-VEC, compared with 18.9 months with GM-CSF.

While these results are encouraging, media claims of a cure for advanced melanoma are misguided. Further research is needed to see how T-VEC compares with existing treatments. It is also not known whether the treatment would work for other types of cancer. 

Where did the story come from?

The study was carried out by a large collaboration of researchers from institutions in North America, including the University of Utah and the Cancer Institute of New Jersey.

It was funded by Amgen, the developers of the technology. The individual researchers report many affiliations with pharmaceutical companies, including Amgen.

The study was published in the peer-reviewed Journal of Clinical Oncology.

The quality of the reporting of this study is somewhat patchy. For example, The Guardian’s statement that, “Patients with aggressive skin cancer have been treated successfully using a drug based on the herpes virus” needs to be set in the correct context.

The study showed only about one in five people given the treatment responded positively to it, so it will not work for everyone.

The claims made by the Daily Express, talking about a cure, are also not supported by the results of this study.  

What kind of research was this?

This was a randomised controlled trial (RCT) investigating treating melanoma with an injectable form of immune therapy.

The immune therapy under investigation is called T-VEC. It is a genetically engineered derivative of the herpes simplex virus type 1 (HSV-1), which causes cold sores.

The derivative is designed to selectively replicate within tumours and produce granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is an important chemical produced during the natural immune response.

It recruits other white blood cells to fight infection or abnormal cells. Injecting a treatment that produces GM-CSF within a tumour should, in theory, boost the immune response to fight the tumour.

This study looked at whether injecting T-VEC directly into melanoma resulted in a better response compared with an injection of GM-CSF. GM-CSF injections are given under the skin, rather than directly into a tumour.

In normal medical practice, GM-CSF injections are used in the treatment of low white blood cell count (for example, in people receiving chemotherapy) to combat reduced immune system function.  

What did the research involve?

This was an international multicentre trial conducted in 64 different locations across North America, the UK and South Africa.

It included 436 adults (average age 63-64) with advanced melanoma that was not suitable for treatment by surgical removal, but could be directly injected with a treatment. People were randomised to receive either T-VEC injections into the tumour or GM-CSF injections under the skin.

T-VEC was given as a first dose, another three weeks later, then once every two weeks. GM-CSF was given once daily for 14 days in 28-day cycles.

Treatment was continued regardless of disease progression for 24 weeks, and after 24 weeks continued until there was disease progression, lack of response, remission or intolerability. At one year, people with stable or responsive disease could continue for a further six months.

The main outcome was disease response rate, defined as complete or partial response that started within the first 12 months and lasted continuously for at least six months. Response was measured through clinical assessment of the visible tumour and body scans.

Other outcomes included overall survival from the time of randomisation, best overall response, and duration of response.

Participants knew which treatment they were receiving, but assessors who examined the outcomes did not know. Analyses were by intention to treat (by the randomised treatment regardless of completion). 

What were the basic results?

Average duration of treatment was 23 weeks for T-VEC and 10 weeks for GM-CSF, and average follow-up time from randomisation to final analysis was just under two years.

Disease response rate was significantly better in people given T-VEC (16.3%) compared with those given GM-CSF (2.1%). This was an almost nine-fold increased odds of response (odds ratio [OR] 8.9, 95% confidence interval [CI] 2.7 to 29.2).

For these people who responded, average time to response was 4.1 months in the T-VEC group and 3.7 months in the GM-CSF group. Average time to treatment failure was significantly longer in the T-VEC group (8.2 months) than in the GM-CSF group (2.9 months).

Average survival was 23.3 months with T-VEC, compared with 18.9 months with GM-CSF. Overall, this was a borderline significant reduction in risk of death, which included the possibility there was no difference (HR 0.79, 95% CI 0.62 to 1.00).

The most common side effect using T-VEC was fever, which affected around half of those treated. This compared with less than 10% of those treated with GM-CSF.

Fatigue affected half of T-VEC treatment patients compared with just over a third in the GM-CSF group. Cellulitis was the only more serious side effect, occurring in a larger proportion of the T-VEC group.  

How did the researchers interpret the results?

The researchers concluded that T-VEC is the first cancer immune therapy to demonstrate benefit against melanoma in a clinical trial.

They say it gave significantly higher disease response rate and just significantly higher overall survival, making this a “novel potential therapy for patients with metastatic melanoma”. 

Conclusion

This randomised controlled trial has demonstrated the effectiveness of a novel injectable immune treatment for advanced melanoma that cannot be surgically removed.

The trial has various strengths, including its large sample size, analysis by intention to treat, and blinding of assessors to treatment assignment, which should have reduced the risk of bias.

It demonstrated that, overall, significantly more people responded to treatment with T-VEC than GM-CSF injections. It also improved survival by an average of 4.4 months, but this only just reached statistical significance, meaning we can have less confidence in this effect.

There are several points to bear in mind, however:

• T-VEC boosts GM-CSF production within the tumour to enhance the immune response, and was therefore compared with GM-CSF injections. However, GM-CSF is not used as a treatment for advanced melanoma. Ideally, the treatment would need to be compared with treatments for advanced melanoma that are currently available – for example, chemotherapy, radiotherapy, and particularly other immune therapies, such as the antibody treatment ipilimumab.
• The treatment has not been shown to “cure” melanoma. Most of the people in this study passed away during the two years of follow-up, but the people receiving T-VEC generally lived slightly longer.
• The treatment is a genetically engineered derivative of herpes simplex type 1 virus. But this is not the same as having been infected with herpes simplex. For example, people shouldn’t wrongly interpret the headlines to think getting cold sores offers protection against melanoma or other types of cancer.
• It is not known whether this treatment could only have potential for the treatment of advanced melanoma, or whether it could have other potential uses for other types of cancer.

Overall, the results of this trial into a potential new immune treatment for advanced melanoma are promising, but more research will be needed.

As with most conditions, prevention is more effective than cure when it comes to melanoma. Avoid overexposure to the sun or other artificial sources of ultraviolet light, such as sun beds, to reduce your risk of skin cancer.

Read more about protecting your skin from the sun

Links To The Headlines

Virotherapy: skin cancer successfully treated with herpes-based drug. The Guardian, May 27 2015

Cold sore virus ‘treats skin cancer’. BBC News, May 26 2015

Genetically engineered virus ‘cures’ patients of skin cancer. The Daily Telegraph, May 27 2015

Herpes Virus Offers Hope Over Skin Cancer. Sky News, May 27 2015

World first as scientists use cold sore virus to attack cancer cells. The Independent, May 27 2015

Could HERPES halt the spread of skin cancer? Genetically modified version of virus ‘kick-starts the immune system and kills diseased cells’. Daily Mail, May 27 2015

Why HERPES virus could hold key to finding a skin cancer cure. Daily Express, May 27 2015

Links To Science

Andtbacka RHI, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. Journal of Clinical Oncology. Published online May 26 2015