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Harnessing the power of the immune system

Published on 09/10/17 at 10:55am

Dr Áine McCarthy, Senior Science Information Officer at Cancer Research UK, discusses the latest efforts to further understand the immunotherapies that have done so much for cancer treatment in recent years, and how they can be pushed to achieve even more.

Our immune system is a powerful defence against foreign bodies like viruses and bacteria, and even cancer. Over the last few years, researchers have exploited its ability to recognise and destroy cancer cells to develop an exciting new range of treatments –immunotherapies. But there remains a large challenge. Not all patients respond to immunotherapies and we don’t know why. For some patients, even when the disease has spread, the treatment can be a cure. For others, it doesn’t work at all. And even for those patients that do respond, these treatments can have harsh side effects.

Teasing apart which patients could benefit from immunotherapies and why, spotting patients who could spare being unnecessarily treated with them, and understanding how the immune system could be better harnessed to kill the disease, are all questions Cancer Research UK is aiming to answer.

Our influence

Cancer Research UK was involved in the discovery that cancer can be caused by infections, identifying the first human cancer virus, the Epstein-Barr virus (EBV). We pioneered work on therapeutic vaccines and developed a successful immunotherapy treatment for EBV-related lymphoma in transplant patients.

The charity also developed the use of antibodies in the form of drugs such as trastuzumab (Herceptin) and rituximab (Mabthera). Rituximab targets a protein called CD20 on the surface of leukaemia and lymphoma cells. The antibody drug sticks to all the CD20 proteins it finds and then cells of the immune system pick out these marked cells and kills them.

Over the last few years, the pace of progress in the field of immunotherapy has accelerated dramatically.  

One of the biggest breakthroughs has been the development of immunotherapies that take the brakes off the immune system – checkpoint inhibitors such as anti-PD-1 and anti-PD-L1. Other approaches involve flagging cancer cells for destruction with antibody drugs, or genetically engineering a patient’s own immune cells to directly target cancers cells with anti-cancer vaccines.

But, while many of these immunotherapy treatments are powerful, they are often untargeted weapons that can sometimes result in a number of potentially serious side effects. Identifying which patients will respond to each of these various forms of immunotherapy remains a challenge.

Ongoing work

Right now, Cancer Research UK is funding a range of research into the immune system and immunotherapy. Professor Christian Ottensmeier at the University of Southampton is looking at what we can learn from the immune system and the tumour microenvironment to help us identify which patients will respond to which treatment and which patients won’t respond to any immunotherapy treatment.

His research group’s most recent study, in collaboration with the La Jolla Institute for Allergy & Immunology, California, mapped out the key immune cells working against cancer cells in patients with early-stage disease.

They looked at a certain type of immune cell called tissue-resident memory T cells. Unlike other T cells which patrol the body, these T cells stay in certain tissues, ready and waiting to fight infections and other foreign bodies – including cancer cells. They saw that these T cells were producing tumour-fighting molecules and could be harnessed to fight tumours from within.

The team took this discovery further by trawling through data from nearly 700 lung cancer patients. Patients with large numbers of this particular type of T cell in their tumours were less likely to die from their disease.

The hope is that immune cell profiling could be carried out during tests to diagnose cancer, potentially helping doctors to make decisions faster on which drugs to give to which patients. This approach could make sure the right patients get the right treatment as soon as possible, and could spare patients unnecessary treatment that’s unlikely to benefit them.

More treatments are urgently needed that can harness immune cells to specifically attack a tumour, while preserving nearby healthy cells, and this is where the forefront of immunotherapy is leading us.

In an exciting discovery last year, Professor Charles Swanton at the Francis Crick Institute and Dr Sergio Quezada at UCL’s Cancer Immunology Unit revealed that cancers contain the seeds of their own destruction. They found that every cell in a tumour shares an identifying flag from the disease’s earliest development that can be recognised and targeted by the immune system. As a tumour grows, it acquires mutations that are displayed as these flags on the surface of the tumour cells.

Professor Charles Swanton co-founded a spin-off company Achilles Therapeutics with an aim to exploit this finding and develop therapies to target mutations that occurred early in a tumour’s development. Because these would be found in every cancer cell in the patient, this kind of personalised approach could be a way to kill all of a patient’s cancer cells and spare healthy tissue.

Despite the growing list of cancers that could be targeted with these treatments, there have been a few that have proved harder to crack, including pancreatic cancer. Pancreatic tumours are densely packed and surrounded by a hard thicket of proteins and cells, and this environment makes it difficult for immune cells to infiltrate and destroy the tumour.

However, Dr Jennifer Morton, a researcher based at the Beatson Institute in Glasgow, in collaboration with scientists from AstraZeneca’s Oncology Innovative Medicines Unit, may have found a way to break down the defences of pancreatic tumours. By studying mice with advanced pancreatic cancer and samples from patients, the researchers showed that a protein, CXCR2, plays a key role in the cancer’s relationship with the immune system.

Blocking CXCR2 with an experimental drug allowed T cells to sweep in and attack the tumour. They showed that the drug extended life in mice where the cancer had already spread, and was particularly effective when combined with chemotherapy.

The researchers also looked at how CXCR2 acts as a homing device for two particular forms of immune cells – neutrophils and myeloid-derived suppressor cells – both of which form an important defence against invaders. In cancer, these two types of cells appear to be attracted to the growing tumour, and enlisted into helping it grow and spread. But the mechanism by which they do this is unclear.

Professor Owen Sansom at the Cancer Research UK Beatson Institute in Glasgow thinks these cells could be helping cancer in a number of ways, and might play different roles in early- and late-stage cancers. Figuring out what these cells are doing at different stages in pancreatic cancer might reveal new ways to switch them from foe to friend.

The future of immunotherapy

Although immunotherapies exploded onto the scene with dramatic results in some patients, there are still a lot of questions left unanswered. How exactly do different parts of the immune system work together? How does the immune system interact with cancer cells? Which patients’ cancers will respond to immunotherapy? And why do therapies not work at all for some patients?

To tackle this, one of Cancer Research UK’s recently announced ‘Grand Challenges’ is centred on immunotherapy. This series of £20 million awards is seeking international, multi-disciplinary teams willing to take on the toughest challenges in cancer. One of the challenges is looking for global, multi-disciplinary teams to create novel tumour vaccinology approaches that establish or enhance successful immune responses beyond what is revealed by current checkpoint therapy.

Ramping up our understanding of the immune system isn’t limited to cancer. Researchers are looking at why the immune system can go wrong in other conditions and how to rectify that. One disease where there is overlap with cancer is arthritis.

To share insights and learnings of the immune system, Cancer Research UK has partnered with Arthritis Research UK to encourage researchers to work together to further understand something called immune homeostasis.

Immune homeostasis is the way the body’s immune system maintains a steady state, so it responds to foreign bodies without causing harm. Understanding how the immune response is fine-tuned to make sure this happens could help us see whether ‘turning it up’ might help limit the growth of cancer cells and the formation of tumours.

By supporting multidisciplinary work and encouraging large international collaborations, Cancer Research UK will continue to push the limits to ensure we reach our ambition of three in four people surviving their cancer by 2034.

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