A new year of expanding research horizons

As a new year of research gets underway, we ask two of our Research Committee Chairs to take stock of the incredible science done over 2021 and tell us what they are excited about in the year to come…

Professor Gerard Evan: “Over the past year or two, hints have emerged that we may be missing a trick in cancer immunotherapy.”

The past few years have seen remarkable advances in cancer treatment that work by redirecting our body’s own immune system to attack cancers.

Immune-oncological therapies have shown incredible promise in treating a wide range of malignant diseases, including melanoma, cancers of the lung, head and neck, advanced oesophageal and stomach cancers and a variety of blood cancers. All these new treatments follow the same general strategy. Our immune systems have evolved to provide highly effective and adaptive defences against pathogen attack, capable of accurately identifying and targeting invading bacteria, parasites and viruses. The key to its specificity is the identification of “foreign” molecular shapes – that is, molecular shapes other than those we have grown up with and are therefore likely to be invading entities.

The rock stars of this immune system are our B and T lymphocytes. B lymphocytes produce antibodies that reside in our blood and secretions that bind and neutralise circulating threats; T lymphocytes identify infected or defective cells and directly kill them. However, both B and T cells have the most remarkable trick up their sleeves – as they respond, they refine their target recognition, by a complex process of molecular trial and error, refining and adapting both the specificity and effectiveness with which they neutralise their interloper targets.

“It is our new-found ability to unshackle adaptive immunity and direct it towards patient’s own cancer that is the great breakthrough”

Cancers are driven by cellular mutations, and these mutations generate novel, foreign structures (neo-antigens) that should in principle be recognisable by our adaptive immune systems. It is our new-found ability to unshackle adaptive immunity and direct it towards patient’s own cancer that is the great breakthrough – a breakthrough that has led to some remarkable cures where all other approaches had failed.

The problem is, however, that these novel immune therapies don’t work reliably against many cancers. They remain a capricious, unreliable and unpredictable therapeutic option in many cancer types and we don’t know why – we don’t know how they work when they do, nor why they fail when they don’t. Despite the intense excitement they have rightly engendered in academia and pharma, the initial advances are tending to stall.

However, over the past year or two, hints have emerged that we may be missing a trick in cancer immunotherapy. While all multicellular animals are in a constant battle against infection, only vertebrates and cyclostomes (jawless fishes like lampreys and hagfish) have (independently) evolved adaptive immunity. The rest of the metazoa makes do with an ancient collateral defence mechanism called innate immunity – a complex web of diverse, defensive cell types that fight infections by attacking generic pattern features of bacterial, fungal, protozoan and viral infection. They also play key roles in identifying damaged or rogue cells and aberrant tissues. The cellular armamentarium of innate immunity also includes sub-types of T and B cells, but they are only feebly adaptive and simply recognise generic features of tissue infection and damage. Other innate immune cells include white blood cells like macrophages and neutrophils, as well as components of connective tissue blood vessels and even nerves.

Importantly, innate immunity is not only a defence against invading pathogens but also monitors tissue normalcy and disruption and plays a major role in responses to physical injury and healing. Huge interest has developed in the diverse and critical roles such innate immune cells appear to play in day-to-day suppression of cancer in healthy individuals, and in the possible therapeutic utility of manipulating innate immune cells to treat cancers. Exciting times lie ahead.

Gerard is Professor of Biochemistry and head of department at the University of Cambridge and Chair of the Cancer Research UK Discovery Research Committee

Professor Kay-Tee Khaw: “The HPV-cervical cancer success is an exemplar of how diverse scientific groups work together.”

Human Papillomavirus (HPV) immunisation was introduced in England in 2008 – and it was at the end of last year that Professor Peter Sasieni and colleagues, in a Cancer Research UK (CRUK) supported study, reported a substantial reduction in cervical cancer from 2006 to 2019.

This finding echoed those reported in 2020 based on a Swedish population registry from 2006 through to 2017. Both studies report the successful prevention of invasive cervical cancer at a population level with a public health measure.

Cervical cancer is the fourth most common cancer in women worldwide, with an estimated 300,000 deaths from cervical cancer annually. Though screening and treatment programmes have been in place for some decades to prevent cervical cancer related deaths, we now know that most cervical cancers can be prevented through vaccination programmes. But it was by no means an easy task to get here.

Early observations that sexual activity was a factor in cervical cancer, and that cancer of the cervix was almost unknown in nuns, led to the hypothesis by Valerie Beral in 1974 that it could be a sexually transmitted infection. She compared mortality trends for cervical cancer with trends in the incidence of sexually transmitted diseases. Human papillomavirus (HPV)16 was first isolated and characterised in 1983 from a cervical cancer specimen. A plethora of studies identifying HPV in historical cervical cancer biopsies, case control studies of HPV virus presence, as well as exploration of molecular mechanisms of HPV-linked carcinogenesis, led to the development of a vaccine in the 1990s.

The FUTURE I and II trials, two international clinical trials of women aged 16-26 years in 24 countries, demonstrated the efficacy of a HPV quadrivalent vaccine in preventing low and high grade cervical lesions. However, clinical trials cannot evaluate vaccine effectiveness against invasive cervical cancer because of the long lead time. Sweden was the first country to introduce HPV vaccinations for girls in 2007, enabling evaluation of effectiveness of a primary prevention public health measure.

“With the increasing ability to conduct large scale detailed studies, including genetic profiling in populations, big data analytics and collaborations, researchers have better tools than ever.”

While much remains to be done to implement effective HPV vaccination globally, the HPV-cervical cancer success is an exemplar of how diverse scientific groups work together, learning from each other, to build on and develop further research and implement findings. Epidemiology studies explored causes, technological advances enabled sensitive and specific DNA characterisation of the virus in tumour samples using PCR, and vaccines were developed based on the finding that the L1 protein of the papillomavirus can self-assemble into Virus Like Particles (VLP) that elicit neutralizing antibodies. Large international collaborations were required for clinical trials, followed by major health service and public health efforts to implement and evaluate population vaccination programmes.

The early ideas that cancer might have an infective origin, and that vaccination might prevent cancer were initially dismissed as implausible. Nevertheless, the mechanisms of carcinogenesis explored in cervical cancer and the clues thrown up by epidemiologic patterns may have lessons for exploring and evaluating prevention of other cancers. With the increasing ability to conduct large scale detailed studies, including genetic profiling in populations, big data analytics and collaborations, researchers have better tools than ever.

Many CRUK supported researchers contributed to the advances in cervical cancer prevention and we look forward to the continuing crucial role of CRUK in encouraging and supporting researchers working towards prevention and treatment of cancer.

Kay-Tee is Professor of Clinical Gerontology at the University of Cambridge, and Chair of the Cancer Research UK Prevention and Population Research Committee

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