Combining a cancer-killing virus with immunotherapy could effectively treat advanced cancers that affect the limbs, a new study reveals.
A modified version of vaccinia virus – the viral component of the smallpox vaccine – was able to switch on the immune system against cancer in rats with sarcoma tumours.
Scientists at The Institute of Cancer Research, London, believe infecting tumours with vaccinia could make immunotherapies work in many more patients – since the immune system is hard-wired to recognise viruses.
The new research is published in the journal published in the journal Clinical Cancer Research and was funded by the charity Sarcoma UK and the Royal College of Surgeons of England.
Uncloaking sarcoma to the immune system
Sarcoma is a cancer of the bone and soft tissue such as muscle and once advanced has very few treatment options, with patients often only surviving for around a year.
When sarcoma affects the limbs it is normally treated with surgery and radiotherapy – but in around 30 per cent of cases, the disease comes back and spreads.
Immunotherapy has shown great promise in many forms of cancer, but can’t yet be used to treat ‘immune cold’ tumours such as sarcoma, which contain relatively few immune cells.
Scientists at The Institute of Cancer Research (ICR) studied sarcomas using tumours in rats and human cells to see whether infection with a vaccinia virus modified to selectively attack cancer cells could uncloak the disease to the immune system.
Isolating the affected limb from the rest of the body
They gave rats a triple cocktail of vaccinia virus, immunotherapy and chemotherapy by isolating the bloodstream in the affected limb from the rest of the body – a procedure routinely used in the clinic to treat sarcoma and melanoma.
The researchers found that all six animals who received the combination therapy followed by surgery for their sarcoma were cured – with the treatment both stopping cancer from coming back in the limb and preventing it from spreading. The vaccinia virus infected and killed cancer cells directly, but also crucially attracted immune cells into the tumour.
ICR researchers and their colleagues at The Royal Marsden NHS Foundation Trust are already running a clinical trial of another form of viral treatment for sarcoma, and next hope to test out the new triple-pronged approach.
The ICR will be exploring use of viruses and innovative combination treatments as part of a pioneering research programme to combat cancer’s ability to evolve drug resistance to be housed within its planned new Centre for Cancer Drug Discovery.
Killing cancer cells and attracting immune cells
The team used a form of vaccinia virus that has had several genes removed so that it selectively grows in and kills cancer cells – by taking advantage of their cellular machinery during rapid growth – but does not infect healthy cells.
Tumours treated with the combination therapy contained three times as many immune cells than controls. More immune cells had also moved into the tumour from the edges, and they showed higher levels of activity.
The virus and immunotherapy were given alongside chemotherapy using a procedure known as isolated limb perfusion, which delivers drugs into the bloodstream after cutting off the blood supply in the limb from the rest of the body.
The researchers have already started a clinical trial in people with sarcoma to assess a different cancer-killing virus called T-VEC, and next hope to test out a triple combination of T-VEC, immunotherapy and chemotherapy.
Study co-leader Professor Kevin Harrington, Professor of Biological Cancer Therapies at The Institute of Cancer Research, London, and Consultant Clinical Oncologist at The Royal Marsden NHS Foundation Trust, said:
“Our study has used the fact that viruses are the ancient enemy of the immune system to infect tumours and spark a strong immune reaction against them.
“We showed that infecting cancer cells with a modified vaccinia virus could kill them directly, but most importantly made tumours much easier for the immune system to spot. It’s a powerful demonstration of the potential both of viruses, and scientifically selected combination treatments, to eradicate tumours.
“The different approaches in our combination therapy are already routinely used to treat sarcoma, or available on the NHS for different cancer types – so I am hopeful that we should soon be able to test them all out together in a clinical trial.”
Exciting development for potential sarcoma treatments
Study co-leader Mr Andrew Hayes, Consultant General Surgeon and Surgical Oncologist at The Royal Marsden NHS Foundation Trust, and Team Leader at The Institute of Cancer Research, London, said:
“This study is a really exciting development for potential sarcoma treatments. Sarcomas are tumours that normally do not appear on the immune system’s radar and therefore can evade the body’s normal defences, even in patients who are treated with immune-stimulating drugs.
“What we have shown is that when we deliver viruses by isolated limb perfusion into the centre of these large tumours and add in an immune-stimulating drug the body’s immune cells enter into the centre of the tumours alongside the virus.
“Not only does this combination treatment appear to be highly effective in treating the visible sarcoma on the limb, but the body’s immune system can now ‘see’ microscopic circulating sarcoma cells and this prevents the development of secondary sarcomas elsewhere in the body.
“We are already running a trial with an oncolytic virus delivered at an operation by isolated limb perfusion which shows that we are able to do run this type of complex surgical study. A study in which we combine an oncolytic virus with an immune-stimulating drug and isolated limb perfusion is the logical next step.”
Richard Davidson, Chief Executive at Sarcoma UK, said:
“The reality for a lot of people in the UK and beyond is that effective treatments for sarcoma cancer are fairly limited.
“Research like this, which drives forward our understanding of the disease, plays such an important role in helping us take those steps towards unravelling the cancer and brings us closer to managing it effectively.”
Reference: Henry G. Smith, et al. PD-1 Blockade Following Isolated Limb Perfusion with Vaccinia Virus Prevents Local and Distant Relapse of Soft-tissue Sarcoma. Clinical Cancer Research (2019) DOI: 10.1158/1078-0432.CCR-18-3767
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