Evolutionary Arms Race could underline Key Immunotherapies

Scientists at The Institute of Cancer Research, London have found that aggressive, highly mutated cancers developed in the gullet and stomach can rapidly evolve strategies to disguise their foreignness from the immune system and evade attack. But their high number of mutations means they look ‘foreign’ to the immune system which leaves them vulnerable to immune attack – as well as susceptible to new immunotherapies.The findings(1) underline the important role of Darwinian evolution in cancer, with the possibility that some of these ‘hyper-mutant’ tumours could in the future help optimise treatment with immunotherapy and other drugs such as chemotherapy.

Funded by Cancer Research UK and the Schottlander Research Charitable Trust, the research  is part of a programme of work at The Institute of Cancer Research (ICR) to understand how cancers adapt and evolve in response to changes in their environment. The ICR is the first organisation in the world to design a drug discovery programme specifically to meet the major challenge of cancer evolution and drug resistance; this will be housed within its new £75 million Centre for Cancer Drug Discovery due to open in the first half of 2020.

Dr Marco Gerlinger, Team Leader in Translational Oncogenomics at The Institute of Cancer Research, London, said: “Our new study has shown that in highly mutated tumours, cancer and the immune system are engaged in an evolutionary arms race in which they continually find new ways to outflank one another.

“Watching hyper-mutated tumours and immune cells co-evolve in such detail has shown that the immune system can keep up with changes in cancer, where current cancer therapies can become resistant – and that we could use immunotherapies to shift the balance of this arms race, extending patients’ lives.

“Next, we plan to study the evolutionary link between hyper-mutant tumours and the immune system as part of a new clinical trial looking at the possible benefit of immunotherapy in bowel cancer.”

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

“Cancer evolution is the biggest challenge in cancer research and treatment today – and deepening our understanding of how tumours evolve in response to treatment is absolutely key to finding ways of overcoming drug resistance.

“This fascinating new study shows how cancers can co-evolve with the immune system, with each responding to changes in the other. Without treatment, cancers will be destined to win this evolutionary arms race, but we can tip the balance in favour of the immune system through carefully designed use of immunotherapy.

“I am keen to see our researchers harness their new insights into cancer evolution to help predict cancer’s response to immunotherapy and ultimately to enhance the way we use immunotherapies to maximise their impact.”

Professor Charles Swanton, Cancer Research UK’s chief clinician, said:

“This study emphasises the importance of understanding how cancers evolve, and highlights likely selection pressures imposed by a patient’s immune system and the developing tumour.

“The challenge in improving outcomes for people with cancer, is to fully understand cancer’s evolutionary rulebook. This will mean studying many more samples from patients with different cancers, as so far these researchers have analysed samples from four patients with a relatively uncommon form of cancer.

“There’s still a long way to go, but we hope that as the rules of cancer evolution are uncovered, we can discover new ways to treat and care for patients with the disease.”

The ICR now has less than £10 million left to raise to finish the Centre for Cancer Drug Discovery and equip it with the state-of-the-art facilities needed for its ambitious Darwinian drug discovery programme.

Published in Nature Communication