The cure within us all

The great hope for cancer research is that we can cajole our own immune system to do the hard work. It has been a difficult road, but the good news is that immunotherapy is starting to pay off…

In 1890’s New York, the bone surgeon William Coley was experimenting with a novel treatment that involved injecting terminally ill cancer patients with a concoction of killed bacterial species. He believed that this would stimulate the immune system to attack the cancer. Miraculously, given his somewhat haphazard approach, he was successful at treating a handful of the 1000 or so cancer patients he experimented on over the course of his research.

Despite this, Coley’s research was dismissed for many years owing to a lack of concrete evidence and competition with the up-and-coming fields of radiotherapy and chemotherapy. Since then our understanding of cancer has grown astronomically. We no longer think of it as a collection of rogue cells but as an entire rogue system, coming together to shape tumour growth and evolution. At the heart of this is the body’s immune system, proving that Coley – sometimes referred to as the forefather of immunotherapy – was truly ahead of his time.

Someone recently described immunotherapy as “the only biological mechanism that can endlessly respond to a changing target”

Researching how we can carefully retune elements of the immune system to recognise cancer has become a major focus of modern immunotherapy research. Someone recently described immunotherapy as “the only biological mechanism that can endlessly respond to a changing target”. That’s spot on. We need to switch away from thinking of cancer as a singular target and move towards a more physiological approach. In practice, that means developing a collective understanding of immunotherapy that applies to all diseases – from bacterial infections and viruses, to autoimmune disease and cancer.

Combinatorial attack

One of the hot topics at the moment is immune tolerance – how the body suppresses an inappropriate immune response. It occurs primarily in tissues that form an interface with the outside world, like the eyes, the skin and the gut. Studying how these remain tolerant to a certain amount of viral or bacterial activity could be central to understanding how tumours exploit these same systems to evade detection.

The UK has some of the best immunotherapy researchers in the world and, increasingly, more of them are shifting their focus towards cancer. It’s this cross-collaborative effort – bringing together different areas of immune expertise – that is really transforming the field. One of the areas really gaining momentum in immunotherapy is combination therapies. Last year nivolumab (Opdivo) combined with ipilimumab (Yervoy) was approved for advanced skin cancer on the NHS, and we’re now working on several related immunotherapy combinations within our own portfolio. For example, Cancer Research UK’s Commercial Partnerships Team has recently formed an alliance with MRC Technology to identify highly novel immunotherapy targets and develop treatments to complement existing ‘checkpoint inhibitors’.

Commercially speaking, these ‘combination approaches’ – which supplement existing antigen inhibitors with small molecules – have the added advantage of being less intensive to manufacture than the ‘gene therapy’ approaches showing promise in non-small cell lung cancer and lymphomas. This also means they are likely to result in new treatments for patients more quickly. This is particularly significant because cost represents a major barrier to widespread use of immunotherapies.

We also need to learn a lot more about why immunotherapies don’t work so well in some settings

Over the next 5-10 years we’re going to see a lot more combination approaches being trialled, reflecting the vast complexity of the immune system, and it is hoped we’re also going to see more progress in less mainstream cancers, like pancreatic. We also need to learn a lot more about why immunotherapies don’t work so well in some settings. There are a few clues emerging – for example we’re finding that lung cancer patients who have smoked actually respond better to immunotherapy, it’s thought because their tumours have a higher mutation rate making them more easily visible to the immune system.

Deep pockets

Despite the fact that expense remains one of the biggest challenges, there has been despite a notable spike in interest from commercial partners wanting to invest in the field. Combination treatments are proving to be very effective within immunotherapy. But with an average price tag of £100-200K per year, per drug, it’s understandable why questions have been raised about these drugs ever getting into mainstream medicine.

Once a patient’s immune system is primed against a cancer, we don’t know how long the effect lasts

There are key questions that we need to answer that can alleviate some of the pressure. First, who should have these drugs? We need ways of pinpointing those who are going to benefit most. And second, how long should we give them for? Once a patient’s immune system is primed against a cancer, we don’t know how long the effect lasts. There is evidence that treatment could be stopped after six months or so and still see a lasting response. But it’s yet to be proven and conducting those trials presents a dilemma because it’s understandably difficult to persuade patients to stop taking a drug that has effectively proved lifesaving.

But despite the challenges, the potential for immunotherapy to unlock cures to otherwise deadly cancers cannot be ignored. This is reflected in the spike we’re now seeing in collaborations involving immunotherapy. In the last 24 months, Cancer Research UK’s Commercial Partnerships Team has embarked on a total of nine new immunotherapy collaborations, with several more in the pipeline for 2017. These bring together Cancer Research UK’s network of world-leading immunology researchers with industry’s technical and financial backing to develop and commercialise new discoveries into treatments that can benefit patients as soon as possible.

For example, we’re involved in the development of a drug called varlilumab that originated from discoveries by Cancer Research UK scientists at the University of Southampton. It’s a successor to the immunotherapy drug ipilimumab, which caused a media storm when it was first revealed as a possible cure for certain patients with metastatic skin cancer. The impact of ipilimumab has been remarkable, but the drug only works for a relatively small number of patients, so much of the research focus is now on broadening that reach.

Brakes off, accelerator on…

One of the ways that tumour cells avoid detection is by suppressing immune responses to stop functional tumour specific T-cells from being produced. Varlilumab targets receptors known to stimulate the immune system, whereas ipilimumab works to block processes that dampen it down. The hope is that combining drugs that both take the brakes off the immune system and push the accelerator could create the type of powerful immune response needed to stop cancer in its tracks. As well as working out how to get past cancer’s defences, another big challenge for immunotherapy is identifying which molecules on cancer cells are the best targets. The Commercial Partnerships Team is involved in the formation of a new company – Achilles Therapeutics – designing new therapies to target truncal tumour neo-antigens. These are unique flags to the immune system that are specific to each patient and present on all cancer cells, rather than just a subset, raising the prospect of a truly personalised approach to lung cancer therapy.

Following a £13.2 million financing round, the Commercial Partnerships Team has granted exclusive rights to Achilles to develop and commercialise neo-antigen technologies arising from Cancer Research UK’s £14million TRACERx study, aiming to track the evolution of patients’ cancers over time, in different parts of their tumours and in response to treatment. Although much of the pharmaceutical interest in immunotherapy so far has involved T-cell technologies, in future we hope to see more treatments focused on the innate immune system. Tumours often hijack innate immune cells, such as macrophages, to promote their own growth. We’re currently involved with a company – Macrophage Pharma Ltd – that is aiming to reverse this process to create an anti-tumour response.

It’s really exciting work that is pushing the boundaries of cancer immunotherapy as we know it. Similarly, there are other immune cells that could be targeted as research into the intricate workings of our immune systems progresses over the next few years. It’s clear that immunotherapy has come a very long way since the days of William Coley. The first glimpses are heartening and there’s more than an air of excitement among industry and academia alike. But in terms of our basic understanding of the role of the immune system in cancer, along with the considerable challenges of navigating an inevitably research intensive route to market, it’s fair to say we still have a long way to go.

The increased availability of microfluidic components and systems, as well as 3D printing, offers a promising future. Microfluidics is spreading its wings and, as its reputation grows, it will no doubt be used further afield in applications that have not yet even been thought of. And that is something to celebrate, for at the heart of the microfluidics revolution, is the overarching desire to put greater control, precision and sensitivity in the hands of scientists, bringing the impossible within reach.

[box type="shadow" align="alignleft" ] About Cancer Research UK’s Commercial Partnerships Team Discoveries by Cancer Research UK’s network of world class scientists may be translated into commercial entities that the Commercial Partnerships Team can then licence out to industry for further development, with all proceeds reinvested back into the charity.[/box]

Authors: Dr Clive Stanway is  chief scientific officer for commercial partnerships at Cancer Research UK.

Professor Stuart Farrow is director of biology at Cancer Research UK’s Therapeutic Discovery Labs (CRUK-TDL).