For most lung cancer patients, the prognosis is bleak. Less than a third of those diagnosed are expected to live beyond a year, and only one in 20 will survive a decade. These mortality rates, one of the worst for any form of cancer, can be attributed to a perfect storm of factors. Lung cancer is often diagnosed at a late stage, it typically occurs in older people who may have other medical conditions and treating the disease can prove exceptionally difficult.
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Luckily, there may be a bright spot on the horizon. Early in 2016, a pioneering new therapy will be tested on NHS patients. Should it prove successful, it will bring hope to the 40,000 people diagnosed with lung cancer in the UK each year.
The £2m trial, funded by the Medical Research Council (MRC), will involve 46 randomly selected participants, all of whom suffer from late-stage, metastatic lung cancer. Typically, these patients would receive chemotherapy – which, in a best-case scenario, extends their lifespan by a matter of months – or opt for palliative care.
"The majority of lung cancer patients present late in the course of their disease," explains Professor Samuel Janes, who is leading the research at University College Hospital in London. "This is because patients get symptoms late, often when their disease has spread to other parts of the body, and so the majority of our patients are offered traditional chemotherapies only."
Children’s cancer death rates in the UK have dropped by 22% over the last decade.
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By GlobalData"These therapies unfortunately work in a minority of patients and are untargeted – meaning they affect the whole body and hence [cause] the common side effects that we hear about."
On the TRAIL of a cure
The new treatment, by contrast, uses stem cells taken from donated bone marrow, which have been genetically modified to encode a protein called TRAIL. TRAIL is a normal part of the body’s immune system, which prevents tumours from forming or spreading. It has long been a focal point for researchers seeking new approaches to cancer treatment.
"With this therapy we are using the cells to target the cancer like a Trojan horse," says Janes. "The cells are attracted to the tumour in a similar way to our white cells being attracted to areas of infection. Once the cells have arrived at the tumour site the cancer cells are then exposed to the killer molecule TRAIL."
The genetic material is encased within a stem cell, meaning it is not degraded by the body, and unleashes the TRAIL protein only once it reaches the tumour sites. This triggers a signalling pathway that kills the cancer cells, while leaving the healthy surrounding cells unscathed.
Cell-based therapies of this kind represent a burgeoning new research area within oncology, with various similar treatments currently on the pathway to the clinic. There have already been several patient studies on leukaemia, which successfully used genetically modified immune cells to blast the disease.
This, however, will be the first cell therapy for lung cancer. So far it has shown success on mice, either fully clearing or significantly reducing their tumours. And following a funding injection from the Biomedical Catalyst (an MRC-managed programme designed to bridge the gap between discovery science and commercial development) it has reached the stage where human trials can begin.
"This clinical trial builds on studies performed in the laboratory showing that the stem cells carrying the killer molecule kill the majority of cancer cells they come into contact with," says Janes. "It will be a phase I/II trial, meaning we will first assess any toxicity of the cells – we don’t expect any as the cells have been given safely before in other clinical trials, and the TRAIL molecule has also been proven safe. We will then assess for efficacy in a randomised trial."
Scaling up production
The patient cohort will receive the gene-cell therapy in combination with traditional chemotherapy to see how their outcomes compare with patients receiving standard care. Each of them will receive nearly a billion cells in total in the course of three infusions, each administered the day after chemotherapy.
Under different circumstances, donor tissue needs to be carefully matched to the recipient, but here it will be possible to use these cells ‘off the shelf’. Because of the way the cells are structured, no problems with rejection are anticipated – irrespective of the patient’s tissue type, they will not induce an immune response.
In the years up to 2018, some 100 billion cells of this kind will be created at the Royal Free Hospital’s cell manufacturing lab in London. While this is good news for the trial, it remains to be seen how feasible the treatment would be if offered to more patients.
If a stem cell theory proves correct, it could dramatically shake up the template for cancer treatment.
"The trial is interesting because it not only challenges the therapy itself but examines the possibility of producing this type of therapy on a larger scale," says Janes. "There are significant manufacturing challenges that will have to be overcome to produce this therapy on a mass scale and we will be examining this as well."
They will need, for example, to ascertain exactly how many cells each patient should receive. Here, the total dose is limited by manufacturing capability and cost, but moving forward the researchers will attempt to ascertain the most therapeutically useful benchmarks.
Should the phase II trial prove successful, the potential is evident. This new therapy could have a major impact on cure rates and survival times for lung cancer patients, therefore reducing the overall morbidity of this deadly condition.
And while a commercially available treatment may still be some way into the future, there are grounds for hope as testing gets underway. With chemotherapy so ineffective, we sorely need new therapies of this kind that shake up the paradigm for lung cancer care.
