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Immunotherapy

By Melissa Bedard, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine

October is a special time of year. The autumn leaves and crisp air mark the beginning of a new academic term. It also marks the annual announcements of the year’s Nobel Laureates, starting with the recipients of the Nobel Prize in Medicine and Physiology.

As scientists, we dream that our work today might revolutionise tomorrow – the kind of achievements that are recognised by a Nobel Prize. My research, like that of many immunologists, is primarily basic in nature. This year’s Nobel Prize in Medicine and Physiology is an exciting reminder that basic immunology discoveries can serve not only as key building blocks to better understanding fundamental immune cell function, but also as therapeutic targets in the fight against immune-mediated diseases.

From the lab bench to the clinic

This year’s recipients are Tasuku Honjo and James Allison for their discovery of PD-1 and CTLA-4 respectively. These two important molecules are expressed on the surface of T cells. Stemming from a branch of immune cells called lymphocytes, T cells have the ability recognise and kill unhealthy cells, such as virally infected cells, with a high degree of specificity. With a better understanding of how certain molecules, such as PD-1 and CTLA-4, control T cell function, scientists have discovered ways of manipulating T cell responses.

These findings laid the foundations for cancer immunotherapy, a revolutionary approach to treat cancer by enabling your own T cells to recognise and kill tumour cells. This strategy has dramatically changed cancer treatment, and has already benefited millions of individuals living with cancer. For example, before the implementation of cancer immunotherapy around 2010, the three-year survival rate for metastatic melanoma patients was just 10%. As of 2017, it was above 50%. Former American president Jimmy Carter received cancer immunotherapy for advanced melanoma that metastasised to the brain and is today cancer-free – just one example illustrating the power of cancer immunotherapy. Not only are patients’ lives extended, but they also have a better quality of life during treatment than with alternative therapies.

Tracing the immunology of cancer

To fully understand why cancer immunotherapy can be so effective, we must go back to fundamental immunology concepts. Immune cells can discriminate between the body’s own cells, termed ‘self’, and foreign pathogens, such as viruses and bacteria, termed ‘non-self’. Based on this discrimination,one’s immune cells will eradicate foreign pathogens while leaving the body’s own cells unharmed. However, the immune cells’ recognition of and response to tumours is a dynamic and complex matter. This is where the Nobel Prize-winning discoveries fit in.

There are several questions to consider when evaluating the immune response to cancer. Firstly, do immune cells infiltrate tumours? Immune cells extensively infiltrate so-called ‘hot’ tumours, whereas ‘cold’ tumours have few to no immune cells within the tumour tissue. Understanding why certain tumours are ‘hot’ while others are ‘cold’ is an intensive area of research, since immunotherapy, including that stemming from Honjo and Allison’s findings, would be most effective for treating ‘hot’ tumours.

Secondly, if present, are immune cells able to kill the tumour tissue? Even in ‘hot’ tumours, immune cells can be dysfunctional and therefore ineffective – an observation termed the ‘Hellstrom paradox’. Since immune cells are heavily influenced by their surroundings, the environment around the tumour might contribute to impaired anti-tumour immune responses. Certain signalling molecules, called cytokines, can shift the type of response mounted by immune cells. These cytokines act as messengers between cells and can be released from multiple cell types (immune and non-immune), including cancer cells themselves. One class of cytokines called interferons often promote tumour killing, while another cytokine, TGF-b, suppresses tumour killing. The relative abundance of such cytokines in the tumour surroundings can tip the balance between a pro- or anti-tumour immune response.  

Binding of specific receptors to PD-1 and CTLA-4 on the surface of T cells (the molecules discovered by the newest Nobel Laureates) inhibits T cell function. Under normal circumstances, PD-1 and CTLA-4 help turn off T cell responses to prevent over-zealous and damaging inflammatory responses (which can contribute to autoimmune diseases like certain types of diabetes). However, in cancer, where T cells must retain prolonged killing abilities, the use of antibodies to block the PD-1 or CTLA-4 interaction with their specific receptors on tumour cells boosts T cell activity so that they remain ‘tumouricidal’. This clinical approach is termed ‘checkpoint therapy,’ the most successful form of cancer immunotherapy to date.

Finally, if infiltrating T cells are effective, can they recognise specific markers on the tumour to kill it? Tumours arise for many reasons, but mutations in the genetic code of individual cells – mutations that cause the cell to multiply unchecked, often contribute to tumour formation. However, these mutations can lead to the production of mutated ‘self’ proteins that no longer resemble normal proteins, and as such immune cells recognise them as ‘non-self’. These mutated proteins are termed ‘neoantigens’ and can be recognised by specific T cells that kill the neoantigen-expressing tumour cells. Identifying and harnessing the power of neoantigen-specific anti-tumour responses is at the forefront of cancer immunotherapy research, especially after Steve Rosenberg’s research group used a cocktail therapy including neoantigen-specific T cells and checkpoint therapy to cure a woman with late stage metastatic breast cancer.

Future directions

Immunologists throughout Oxford, including those at the MRC Human Immunology Unit (MRC HIU) at the MRC Weatherall Institute of Molecular Medicine (MRC WIMM), are playing their part in advancing cancer immunotherapy research, particularly in addressing the three questions previously mentioned. Student-led research has centred on a molecule expressed by tumours that binds a receptor on T cells, similar to PD-1, which prevents T cells from infiltrating tumours. This interaction impairs T cells’ physical mobility by altering the cells’ actin cytoskeletons; collaborations between multiple labs in Oxford guided this research component. Other research also ongoing here in Oxford focuses on: (a) the affect of engineered antibodies against another inhibitory molecule, BTLA; (b) analysing tumour-specific T cell populations in melanoma patients over the course of their checkpoint therapy; and (c) fine-tuning the production of PD-1 on T cells to elicit effective anti-tumour responses while limiting a damaging inflammatory response.

Work at the MRC HIU also assesses how the tumour microenvironment contributes to anti-tumour immune responses. We investigate how immune cells are affected by stressful conditions, such as a lack of amino acids or oxygen. Based on these studies, we are assessing the therapeutic potential of manipulating metabolic enzymes differentially expressed in tumours versus immune cells.

Finally, there is ongoing and promising work on neoantigen discovery through understanding the mechanisms of neoantigen expression in ovarian cancer, melanoma, and glioblastoma multiforme, a type of brain cancer.

Final thoughts

All of this exciting immunology research, from basic mechanisms of immune cell function to translation studies, will contribute to a growing pool of knowledge that can guide therapeutic interventions for cancer. This year’s Nobel Prize in Medicine illustrates that basic discoveries in fundamental immunology paired with creative and aspirational thinking can have far-reaching implications for the future of medicine. Scientists at the MRC WIMM, including myself, had the pleasure of hearing Dr Honjo speak about his work last year. As compelling as his research was (and is), it was equally inspiring to see that Nobel Prize winners are fellow, hard-working scientists with the curiosity and appetite to see how far their ideas will go.

Saiga antelope

Ahead of a symposium organised by the Oxford Martin School on the Illegal Wildlife Trade, and international IWT conference hosted in London this week, Diogo Veríssimo, from Oxford University’s Department of Zoology, reveals how campaigns have attempted to influence harmful consumer habits.

What do elephants, sharks and pangolins have in common? They are all threatened by the illegal trade, be it for their ivory teeth, fins or scales.

Around the world the use of animal and plant parts is increasingly being recognised as a threat not only to wildlife but also to people, as illegal or unregulated movement across vast regions can spread deadly diseases such as Ebola or SARS. While most work to curtail the illegal wildlife trade has focused on law enforcement and surveillance, there are increasing efforts to influence the consumers of these products.

Demand is a key part of any illegal market and while it exists it will be impossible to manage. Conservationists are therefore increasingly working to influence consumers by shifting their buying habits. Together with Anita Wan, currently at Sun Yat-sen University in China, we reviewed the data on this conservation approach, and the results were recently published in Conservation Biology.

Captive Macaw Captive Macaw

Diogo Verissimo

We found 236 campaigns featuring well-known species such as elephants, tigers and rhinos but also lesser-thought-of turtles, tuna, rosewood timber, macaws and saiga antelopes. Surprisingly, the majority of campaigns were focused on seafood, with sharks being the most represented animal.

In addition, we found that at continental level, more than a third of campaigns were found in Asia. This is perhaps unsurprising given the significance of key consumer countries such as China or Vietnam. Less anticipated, however, was that the United States held the most campaigns at a national level. This could be explained by the fact that many conservation organisations working on this issue are based there.

One of the key challenges highlighted by this report was that little is known about many of these demand reduction campaigns. For example, we could not pinpoint what year 10% of them took place, and only one quarter of campaigns reported their outcomes.

These gaps in information are not unique for such campaigns, but they now form key priorities for researchers who are coming together next week an Evidence to Action: Research to Address the Illegal Wildlife Trade. This symposium will take place  at the Zoological Society of London on October 9, and is co-lead by the Oxford Martin Programme on the Illegal Wildlife Trade (Department of Zoology of the University of Oxford), in collaboration with several other UK Universities and NGOs.

These group of researchers and practitioners have also authored a policy brief that discusses the research gaps surrounding the illegal wildlife trade. This brief will feed into the Illegal Wildlife Trade Conference in London, an international summit organised by the UK Government taking place on the 11 and 12 of October.

Find out more about an Evidence to Action: Research to Address the Illegal Wildlife Trade.

Find out more about the Illegal Wildlife Trade Conference.

Watch the Oxford Sparks video on protecting elephants, protecting humans

Find out more about how the University of Oxford is working with local communities and using the latest technology to help people and wildlife to co-exist, via the Oxford Sparks website.

Overcoming the challenges of Rural Surveys in Developing Countries

Field researchers, Dr Giacomo Zanello, Dr Marco Haenssgen, Ms Nutcha Charoenboon and Mr Jeffrey Lienert explain the importance of continuing to improve survey research techniques when working in rural areas of developing countries.

News about big data and artificial intelligence can leave the impression that a data revolution has made conventional research methods obsolete. Yet, many questions remain unanswerable without working directly with (and understanding) the people whose lives we are interested in. In development studies research, survey research methods therefore remain a staple of data generation, and survey data generation itself remains an active field of debate. In today’s blog, four researchers showcase recent methodological advances in rural health survey research and the advantages they bring to conventional research approaches.

Reaching People at the Margins, 25% off! (Dr Marco J Haenssgen, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine)

Generating representative data from rural areas of developing countries is a real challenge because often we lack detailed and dependable information on the local population, which makes drawing a sample very difficult. However, recent technological revolutions that we are rather familiar with – the Internet, mobile phone technology, satellite navigation – can also facilitate our work in survey research. Satellite maps in particular help us to:

(1) Select villages more rigorously: We can use satellite maps to generate or verify geo-coded village registers (e.g. censuses or the US National Geospatial-Intelligence Agency) to draw geographically stratified samples. Geo-stratification ensures that we do not accidentally select only “easy” villages that represent less constrained lifestyles in the rural population.
(2) Identify and select houses within the villages more inclusively: Conventional methods to draw a sample of households require either a very laborious enumeration process by going from house to house to establish a sampling frame, and/or are likely to exclude households and settlements at the fringes of a village (e.g. a “random walk”). By using satellite images to enumerate all houses in a village, not only do we save a lot of time and money, but we can also ensure that all parts of a village are represented fairly.
(3) Reach survey sites more efficiently: The logistical benefits cut as much as 25% off the conventional survey costs and time, which can save up to £5,000 for a PhD-level survey (400 respondents in 16 villages) and £40,000 for a medium-sized two-country survey (6,000 respondents in 139 villages).

We need to appreciate that satellite-aided sampling approaches are only an addition to our survey toolkit. They do not work well in urban areas, with mobile populations, or in regions that we are not familiar with. But where they work, they are a real alternative to conventional survey approaches and can make projects feasible that would otherwise be prohibitively expensive, without compromising quality.

Taking Energy Measurement From the Lab to the Field (Dr Giacomo Zanello, School of Agriculture, Policy and Development, University of Reading)

How much energy do you burn during the day (at your job, doing household chores, or at the gym) and is this “energy expenditure” in balance with the calories you take in with your food and drinks? Historically, to answer this question, participants had to spend time in a sealed chamber in a lab which measures the change in oxygen levels while performing activities. While this provides an accurate estimate of energy use, this method is quite impractical to understand real-life settings, particularly for remote areas in a developing country context. It is in these contexts where calorie deficits are most pressing, and yet we do not know much about farmers’ energy use, differences across gender and age groups, or variations of energy use across the seasons and during health or climate-borne adversities.

Recent technological advances allow the measurement of energy expenditures of free living populations to a scale and within a budget inconceivable few years ago. Using Fitbit-like accelerometers we can capture people’s movements and use this information to estimate calorie expenditure. By wearing these devices we follow people’s activities throughout the day, weeks, and seasons and use this information to estimate their energy use. This new glimpse into how people spend their energy can improve health research in multiple domains, for example:

• Having a more accurate assessments of the incidence, depth and severity of undernutrition and poverty,
• Estimating energy requirements for specific livelihood activities, or
• Studying the effect of health conditions and illnesses on livelihood activities.

These are just some possibilities, and the data collected through this innovative methodology extends beyond health-focused research. It also enables us to learn more about how labour is distributed within rural households in developing countries, or measure production in the household and the “informal economy” to produce better estimates of the size of rural economies.

Taking energy measurement from the lab to real-life settings is not without complications. We have to make careful decisions about the devices we use (e.g. easy to wear, not requiring user interaction, not attracting too much attention), build a trusting relationship with our research participants, and acknowledge that even accelerometer-generated data only offers a partial view into energy expenditure and daily activities. Yet even this partial view can afford a completely new understanding of people’s rural livelihood.

A Qualitative Research Update for Social Network Surveys (Ms Nutcha Charoenboon, Mahidol-Oxford Tropical Medicine Research Unit)

Health and treatment hardly take place in isolation – people around us influence our behaviour, give us advice, or lend us a ride to the hospital. Public health information campaigns, too, are subject to people’s relationships because they might be communicated further or even be instrumentalised for political purposes. Perhaps it is no surprise then that there are calls for more social network research on health in developing countries, but such research faces difficult questions, like how do we ask elicit the names of people in these networks, and how we can match these names in place where one person might be addressed in several different ways (e.g. “Old Father,” “Leader,” Yod Phet, and Ja Bor).

How can we overcome such difficulties? One possibility is cognitive interviewing, consisting of a set of interview techniques to test and interpret survey questions. Among others, interviewees are given survey questions and asked to “think out loud” on how they understand and answer the question, to paraphrase the question in their own words, or to explain village life and the local context. Such information gives researchers a better grasp of local social networks, living arrangements, and people’s understanding of social network questions. In our study in rural Thailand and Lao PDR, it enabled us to drop irrelevant questions, add questions to map health social networks more comprehensively, and to identify mechanisms to locate named contacts within the village more effectively.

But beware of surprises when you carry these methods over to developing country contexts because they tend to assume Western communication norms. Our research participants felt uncomfortable when asked to articulate their thought processes or to answer “why” questions. To cope with such complications, the methods themselves need to be adapted to context, for example by being more closed-ended and by adopting more conventional semi-structured interview techniques.

Shining New Light on Health Behaviours (Mr Jeffrey Lienert, Saïd Business School and National Institutes of Health)

When people get sick, they do not just make a one-off treatment decision like “I’ll go to a clinic / a private doctor / a pharmacist” and stick to it for the remainder of their illness until they are cured. Rather, they go through several phases. For example, a person might first wait and see if it the illness would not go away by itself, then later decide to buy some painkillers to cope with it, visit a private doctor when things do not get better, then lose hope in modern medicines and visit a traditional healer. We gain a lot of information about people’s behaviour if we collect such data on treatment “sequences.”

Not only is it rare for studies to record treatment sequences at all, but there are also no agreed tools for their analysis. First ground has been broken with sequence-sensitive analyses to produce more accurate typologies of behaviour, but we can go further and apply network analysis techniques to make maximal use of sequential data. More detailed analyses can differentiate between the individual steps, explore whether sequences of behaviour resemble each other across people, and which kind of social network is most decisive for such a resemblance. The downside of these arguably more complex analyses is the technical skill required to perform them, but once these methods become more established, they will be able to us to give more detailed (and realistic!) behavioural profiles of different settings and social groups with revolutionarily new insights for health policy.

Methodological innovation enables easier, more precise, and new ways of understanding human behaviour. That does not necessarily mean “big data” and algorithms. Innovation also arises from new combinations of conventional methods with other established techniques and new technologies. Combining rural health surveys with satellite imagery and accelerometers, social network surveys with cognitive interviewing, and healthcare access data with social network analysis does not just keep the methodological debates in survey research alive. It also enables new research, new questions, and a new view on human behaviour.

This blog entry derives from the authors’ contributions to the ESRC NRCM Research Methods Festival 2018 Conference in Bath, drawing on research from the projects Antibiotics and Activity Spaces (ESRC grant ref. ES/P00511X/1), Mobile Phones and Rural Healthcare Access in India and China (John Fell OUP Research Fund ref. 122/670 and ESRC studentship ref. SSD/2/2/16), and IMMANA Grants funded with UK aid from the UK government (ref. #2.03).

Agreeing to disagree about medical treatment for children

Professor Dominic Wilkinson, Professor of Medical Ethics at the University of Oxford and a Consultant in newborn intensive care at the John Radcliffe Hospital, Oxford, discusses the ethical issues around providing medical treatment for children when parents and doctors disagree.

The fraught life and death cases of Charlie Gard and Alfie Evans, reached global attention in 2017 and early 2018. They led to widespread debate about conflicts between doctors and parents, and about the place of the law in such disputes. Changes to the law in response to these high-profile cases are currently being debated in the House of Lords.

In 2016, Professor Savulescu of the Oxford Uehiro Centre for Practical Ethics wrote an editorial for the Lancet medical journal strongly criticizing the court’s decision, and arguing that Charlie Gard should be allowed to travel to America for experimental treatment. He argued that Donald Trump and the Pope were right to support Charlie’s family. In the same issue of the Lancet, I took the opposing view, supporting Charlie’s doctors, and arguing that Charlie should be allowed to die. Professor Savulescu and I are colleagues and long-time collaborators.

Over the ensuing months, while the appeals for Charlie Gard were heard in the courts, Savulescu and I conducted a vigorous debate in academic journals and in the media about the rights and wrongs of the Gard case. Over time, we found areas of agreement, as well as areas of reasonable disagreement.

In a newly published book, Professor Julian Savulescu and I examine the ethics of medical treatment disputes for children, as well as outlining our own professional disagreement on the Gard case. At one level, this is a rigorous analysis of the rights of parents, the harms of treatment, and the vital issue of limited resources. From opposite sides of the debate about treatment for Charlie Gard, we provocatively outline the strongest arguments in favour of and against treatment. We also outline a series of lessons from the Gard case and propose a radical new ‘dissensus’ framework for future cases of disagreement.

This case also illustrates some of the distinctive and challenging features of ethical debate in the 21st century. We have shown that it is possible for those who find themselves at opposite ends of an issue to find common ground. Indeed, disagreement about controversial ethical questions is both inevitable and desirable.

There is a need for sensitive, rational debate within our community about how to fairly address disagreements about treatment between health professionals and families. That debate cannot, now, help Charlie Gard or Alfie Evans. It can, though, help current and future children with serious illnesses.

It can support their families to access desired treatment, within limits. It can help health professionals to be able to advocate for the best interests of their patients. It can help doctors to maintain relationships with families (even if not always seeing eye to eye). It can help society to understand what is at stake, why these disagreements are so difficult, so vexed, and so inevitable.

In difficult ethical debates, there is sometimes a desire to reach consensus or agreement on the right thing to do. But that can be a mistake. On questions of deep ethical values, there will always be disagreement. We need to embrace dissensus, not consensus. We should be prepared to disagree

‘Ethics, conflict and medical treatment for children: from disagreement to dissensus,’ is published by Elsevier.

Professor Julian Savulescu is Professor of Practical Ethics in the Oxford Uehiro Centre for Practical Ethics at the University of Oxford. Professor Dominic Wilkinson is Professor of Medical Ethics at the University of Oxford and a Consultant in newborn intensive care at the John Radcliffe Hospital, Oxford. Wilkinson and Savulescu are medical doctors as well as experts in medical ethics.

Coral reef

New research published in Nature Ecology & Evolution from the Department of Zoology at Oxford University aims to show how big data can be used as an essential tool in the quest to monitor the planet’s biodiversity.

A research team from 30 institutions across the world, involving Oxford University’s Associate Professor in Ecology, Rob Salguero-Gómez, has developed a framework with practical guidelines for building global, integrated and reusable Essential Biodiversity Variables (EBV) data products.

They identified a ‘void of knowledge due to a historical lack of open-access data and a conceptual framework for their integration and utilisation'. In response the team of ecologists came together with the common goal of examining whether it is possible to quantify, compile, and provide data on temporal changes in species traits to inform national and international policy goals.

These goals, such as the Sustainable Developmental Goals (SDG) of the United Nations, have become fundamental in shaping global economic investments and human actions to preserve and protect nature and its ecoservices.

Essential Biodiversity Variables (EBVs) have been proposed as ideal measurable traits for detecting changes in biodiversity. Yet, the researchers say, little progress has been made to empirically estimate how EBVs in fact change through time at the regional and global scales.

To overcome this, Rob Salguero-Gómez and his international collaborators have developed a framework with practical guidelines for building global, integrated and reusable EBV data products of species traits. This framework will greatly aid in the monitoring of species trait changes in response to global change and human pressures, with the aim to use species trait information in national and international policy assessments.

Salguero-Gómez says: 'We have for the first time synthesised how species trait information can be collected (specimen collections, in-situ monitoring, and remote sensing), standardised (data and metadata standards), and integrated (machine-readable trait data, reproducible workflows, semantic tools and open access licenses).'

This latest review provides a perspective on how species traits can contribute to assessing progress towards biodiversity conservation and sustainable development goals. The researchers believe that big data is one of the keys to address the global and societal problems from security food, to preventing ecoservice loss, or effects of climate change. 

They say that the operationalization of this idea will require substantial financial and in-kind investments from universities, research infrastructures, governments, space agencies and other funding bodies. ‘Without the support of the Max Planck Institute for Demographic Research, NERC, Oxford, and the open-access mentality of hundreds of population ecologists, our work with COMPADRE & COMADRE would not have been possible,’ says Salguero-Gómez.

The integration of trait data to address global questions in ecology, evolution, and conservation biology is one of the main themes in Salguero-Gómez’ research group, the SalGo Lab.

This work was funded primarily by the Horizon 2020 project GLOBIS-B of the European Commission.

 Read the full paper in Nature Ecology & Evolution.