Innovations in Immunology - Q2 2019

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Innovations in Immunology HEALTHAWARENESS.CO.UK

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Progress in vaccines against malaria, HIV and TB three major infections in Africa FAITH OSIER President-elect, IUIS

CLIVE GRAY Past president, SAIS Secretary-general, FAIS

HENRY MWANDUMBA President, FAIS

HIV/AIDS, tuberculosis (TB), and malaria are three major infections that globally lead to approximately five million deaths every year, with the majority of these occurring in sub-Saharan Africa.

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espite global efforts at prevention and improving control, the public health impact of these diseases is still huge. Medicines are the mainstay of control efforts, but drug resistance is a constant threat.

Effective vaccines are urgently required and would add substantially to the ongoing efforts to curb these diseases.

The first vaccine against malaria to receive a positive opinion from the European Medicines Agency will soon be tested in implementation trials in three African countries: Kenya, Malawi and Ghana.

This vaccine targets a single protein from the pre-erythrocytic stage of the parasite life-cycle and protects an estimated four of ten individuals vaccinated. In areas of where the intensity of malaria transmission is high, the benefits of this modest efficacy are welcome.

It is clear though, that it is not yet the magic bullet for malaria, and efforts to develop vaccines targeting the erythrocytic stages, and those that block transmission to mosquitos continue

vigorously. Sub-unit vaccines containing antigens from multiple stages, as well as attenuated whole-organism vaccines also continue to be explored.

New on the horizon is the prospect for monoclonal antibodies, which would provide short-term protection.

HIV vaccine is a top priority An efficacious HIV vaccine remains one of the top priorities to curb the high rates of viral transmission globally, and more so in sub-Saharan Africa. The anti-retroviral therapy (ART) roll-out in many African countries, through a variety of funding sources, has been a game-changer for those people who are HIV-infected.

A combi n at ion of a n ef fe c t ive vaccine along with ART and pre-exposure prophylaxis (PrEP) can make huge in-roads to curbing high transmission rates.

Mu lt iple s t r ate g ie s a r e b e i n g employed, which range from reverse-eng ineering broadly neut ra l isi ng a nt ibod ies, usi ng novel viral vectors carrying HIV genes and

employing a heterologous prime-boost approach. The moderate success of 31% efficacy in the RV144 Thailand trial using canarypox priming and antigp120 boosting is being repeated in Africa. The combination is immunogenic and elicits binding IgG to the V1/ V2 loop of Env, shown to be a correlate of reduced risk of HIV acquisition in the RV144 trial.

TB is the leading cause of death worldwide – but BCG vaccine isn’t enough Current measures to control tuberculosis (TB), the leading infectious cause of death worldwide, are similarly insufficient and underscore the urgent need for effective TB vaccines to augment existing interventions.

Bacille Calmette-Guerin (BCG) is the only licenced TB vaccine and has been available since 1921. While neonatal BCG vaccination can provide partial protection against severe TB disease in infants and young children, it is poorly protective against adult and adolescent pulmonary TB.

For the last decade, efforts to develop new TB vaccines using a variety of platforms and vaccination strategies have intensified. These efforts include adjuvant proteins, vectored subunit vaccines and whole cell vaccines for TB disease prevention, early life immunisation, boosting BCG and as adjunct i m mu ne t herapies to re duce t he duration of drug therapy.

There is genuine enthusiasm in the field and the results of the M72/ AS01E vaccine trial published recently are a cause for optimism. This vaccine contains an immunogenic fusion protei n (M 7 2) der ive d f rom t wo Mycobacterium tuberculosis (Mtb) antigens (MTB32A and MTB39A), adjuvanted with AS01E. These infectious diseases provide fertile ground for active research and cont i nued col laborat ion bet ween African and international scientists will be instrumental for more progress.

Read more at healthawareness.co.uk

Immunology at the cutting-edge AN INDEPENDENT SUPPLEMENT BY MEDIAPLANET

Immunology is trailblazing a path of medical discovery; there has never been a more exciting time to be an immunologist.

What are the emerging areas that experts think will have a significant impact on our ability to treat disease?

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mmunology is at the cutting-edge of medical discovery, with many new biological agents now translating from bench to bedside. As our understanding of how the immune system functions has grown, so too has our knowledge of the many different areas of health that the immune system affects.

Alongside this, the therapeutic possibilities for diseases that may be amenable to treatment through harnessing the immune system have also increased hugely. This has led to a number of emerging areas where we can bring new knowledge on the intricacies of immune functioning to increase understanding of disease mechanisms and therapeutics and drive significant steps forward for the benefit of patients.

Promising research areas in white blood cell research One exciting development is the discovery that white cells, the enforcers of the immune system, have intrinsic brakes

ARNE AKBAR President, British Society for Immunology

that stop them from functioning. This is a safety mechanism that prevents over-activation of the immune system.

However, by disengaging these brakes therapeutically in patients with certain types of cancer, immunity against the tumour is enhanced significantly, to the benefit of the patients. Indeed, the 2018 Nobel Prize in Physiology or Medicine was awarded for this discovery and, in the coming years, it will be exciting to see how the therapeutic potential of this approach develops.

Research looks at exercise and diet affecting the body’s nutrient resources Another area of major interest is in understanding the way that white cells utilise energy to elicit different functions. This new research area, termed ‘immunometabolism’, is providing us with exciting insights into the complex relationship between immunity and metabolic reprogramming. This is linked to available

nutrient resources in the body and this area of research may provide the basis of how diet and exercise could regulate immune responses.

A third area of intense interest is how microbes that co-exist with us on our skin, in our gut and in our airways – our microbiome – shape the function and type of immune cells that are found at these sites. Antibiotics don’t only kill pathogenic bacteria but destroy these ‘friendly’ microbial communities as well.

Therefore, while the use of antibiotics is essential in certain situations, overuse of these agents may be detrimental in some circumstances, and may also lead to the development of antibiotic resistance in certain organisms. This requires further investigation.

F i n a l l y, t h e i m m u n e s y s t e m operates on a tightrope; insufficient immunity may lead to the increased incidence of infections and cancer, while excessive immunity, akin to ‘friendly fire’ may lead to the development of

autoimmunity. Understanding how this balance of sufficient but not excessive immunity is regulated will ultimately enable immunologists to manipulate the immune system safely in many disease areas.

Big data and genome editing pose exciting opportunities for research There has never been a more exciting time to be an immunologist, with new technologies in ‘big data’ and genome editing now complimenting detailed animal and human studies.

However, we still have much to learn and many questions are, as yet, unanswered. The opportunities for immunologists to innovate are ripe and the next few years should prove an exciting time for immunology research.

Read more at healthawareness.co.uk

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Time for the single-cell revolution

MIKE STUBBINGTON Computational Biologist, 10x Genomics

We are standing on the cusp of a ‘single-cell revolution’ that could increase our understanding of the immune system exponentially.

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he technolog y, developed by 10x Genomics, allows scientists to analyse the paired antigen receptors of an individual T-cell or B-cell, uncover which proteins are on the cell’s surface, and ‘match’ the antigens that will attach to it, while simultaneously measuring gene expression.

“This is really exciting because it gives you a holistic view of what's going on,” said Stubbington, Computational Biologist at the company.

“You get this complete view of the cell: which genes are switched on, which proteins are on its surface, what its T-cell receptor sequence is, and if that T-cell receptor binds to one of the antigens you are interested in.”

It’s an “incredible amount of information”, and the approach allows for tens of

thousands of cells to be analysed at this minute level with high-resolution.

Public data to help researchers worldwide 10x Genomics is about to release a database of more than 100,000 individual T-cells and their ability to recognise 44 different antigens. The data set took less than a week to compile.

Stubbington said: “We are releasing the data so researchers can understand how they might conduct experiments and what some of the difficulties might be. We really want to work with the community to drive this new world forward.”

So far, 10x Genomics has “only scratched the surface”, but the approach could be game changing in areas focused on diagnostic or therapeutic development.

Game changing potential “Imagine if we could ask, ‘what is the immune system responding to?’

Imagine designing a complete, novel, synthetic antigen receptor that recognises your immune response target.

“That gets you into the world of novel immunotherapy and being able to rationally design those treatments,” said Stubbington, explaining that a better understanding of cellular biology and disease would also greatly benefit research.

The biggest challenge to achieving such heights, however, is the ability to see a clear path through so much information.

“As you scale up the amount of data, it gets very complex very quickly, but I think we are at a really good place in terms of computation approaches,” said Stubbington.

With machine learning offering ever more sophisticated ways of extracting patterns from high-dimensional data sets, the time is right for the single-cell revolution, he concluded.

Byline: Amanda Barrell

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Read more at 10xgenomics.com/ immunology

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Checkpoint inhibitory receptors keep the immune system in check Cancer checkpoint blockade - this year’s Day of Immunology theme – has revolutionised cancer treatment for many patients.

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The immune system is like many things in life, it works best when it is perfectly balanced - too little a response leaves us susceptible to infection, while too much can result in the development of autoimmunity.”

ver y yea r on Apr i l 2 9 t h, t he European Federat ion of Immunological Societies – EFIS – celebrates the Day of Immunology; a day designed for European and international scientists to bring immunology into the public domain – a key mission of EFIS. This year’s topic is cancer: checkpoint blockade. It is a perfect opportunity for immunologists to show the public the importance of immunological research and how it can revolutionise treatment of diseases that have exhausted all other treatment options.

Furthermore, by translating our basic research into clinical success, such as with the introduction of cancer checkpoint blockade therapy in treating late-stage metastatic cancer, we can bring much needed new hope for many patients suffering from cancer and other diseases.

clinically targeted, inhibitory receptors are cytotoxic T lymphocyte associated antigen-4 (CTLA-4, CD152) and programmed cell death-1 (PD-1, CD279).

CTLA-4, expressed on naive and memory T cells, competes with the stimulatory receptor CD28, but has far higher affinity for the shared ligands CD80 and CD86, resulting in its ability to outcompete CD28 for ligand binding. PD-1 is also expressed on T cells, among others, and binds to its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273).

Immune checkpoints The immune system is like many things in life, it works best when it is perfectly balanced - too little a response leaves us susceptible to infection, while too much can result in the development of autoimmunity. This balancing control comes from the inbuilt ‘fine-tuners’ of the immune response: checkpoint inhibitory receptors.

These receptors inhibit the activation of immune cells such as T cells, following antigen/MHC presentation by terminating downstream signalling cascades. The best described, and

Cancer and inhibitory checkpoint blockade One mechanism by which cancer deactivates the immune system involves subversion of immune checkpoints. Cancer cells have been found to express ligands that bind to the inhibitory receptors on tumour-infiltrating immune cells, effectively ‘switching-off’ the immune response. In order to ‘switch-on’ these cells, anti-CTLA-4 and anti-PD-1 antibodies have been generated to block these inhibitory receptors and unleash the immune response.

The first anti- C T L A- 4 antibody

ANDREAS RADBRUCH President, the European Federeation of Immunological Societies (EFIS)

(ipilimumab) was given FDA approval in 2011 for patients with metastatic melanoma and was found to enhance survival in a significant number of patients.1 Anti-PD-1 antibodies (pembrol i z u mab a nd n ivolu mab) were licenced in 2014 and have proven successful in the treatment of numerous types of cancer.1 Given the advanced stage of many of these cancers, such antibodies have completely revolutionised cancer treatment for many patients.

Autoimmune responses following checkpoint blockade Switching off the immune brakes is beneficial for the destruction of cancer cells, but it is not without consequences.

Immune responses are fined-tuned for a reason, with one of the pitfalls of checkpoint blockade therapy being the development of immune-related adverse events (irAEs), essentially autoimmune-like reactions resulting from the lack of inhibition of checkpoint inhibitors.

Such irAEs are not rare, with severe irAEs (grade 3 and 4) occurring in 55% of metastatic melanoma patients undergoing combined CTLA-4 and PD-1 antibody therapy1. irAEs can be lethal, although thankfully, rarely, and in most cases, discontinuation of treatment or addition of immunosuppressive t herapy is enough to control the irAEs. While most patients no longer experience symptoms following the end of therapy, unfortunately, there are instances when autoimmune diseases develop from irAEs.

Checkpoint blockade treatment for autoimmunity Not surprisingly, given the already activated state of the immune system in autoimmune patients, use of antiCTLA-4 blocking antibodies in cancer patients with pre-existing autoimmune conditions, exacerbated the autoimmune response in a quarter of patients.2 While the development of autoimmune diseases is clearly multifaceted, much can be learned from checkpoint blockade therapy in cancer patients for the treatment of autoimmune conditions. Indeed, a CTLA-4-Fc fusion protein (abatacept) was the fi rst checkpoint targeting dr ug used for the treatment of rheumatoid arthritis and has been found to have clinical success. 3 Balancing the immune system is key Clearly, the maintenance of a balanced i m mu n e s y s t e m i s t h e o p t i m a l situation in most instances. However, as scientists and clinicians, we are now able to manipulate this balance as ev idenced by targeting in hibitory receptors, providing us with an invaluable immunological tool for the treatment of diseases such as cancer and autoimmunity.

Headshot credit: Gero Breloer Byline: Mairi Mcgrath Read more at healthawareness.co.uk

1: Larkin, J., et al., Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med, 2015. 373(1): p. 23-34. 2: van der Vlist, M., et al., Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us? Nat Rev Rheumatol, 2016. 12(10): p. 593-604. 3: Blair, H.A. and E.D. Deeks, Abatacept: A Review in Rheumatoid Arthritis. Drugs, 2017. 77(11): p. 1221-1233.

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How to translate discoveries into treatments fast MARIO ASSENMACHER Senior Manager, Research and Development, Miltenyi Biotec

Ensuring patients receive the benefits of ground-breaking basic science discoveries as quickly as possible requires intellectual and technological collaboration.

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he latest hot topic in immuno-oncology – following checkpoint inhibitors - is CAR-T cell therapy. It went from the very first research publication in 1989, through development and into clinic in under 20 years.

M a r i o A s s e n m a c h e r, s e n i o r manager of research and development at Miltenyi Biotec, which specialises in systems that empower biomedical research, said: “One of the first translational successes, when the fi rst patients showed that this approach worked, was in 2011”.

“It was then just six years until the first product was approved in 2017. That was very fast."

“It’s a perfect example of how innovation can make a difference and be really disruptive. It’s about changing the paradigm and improving on areas where our therapeutic options are still far from perfect.”

Speeding up the bench-to-bedside time frame Moving from bench to bedside is not always a straightfor ward process, however, meaning discoveries can often get “stuck” in academia.

The reasons for this, said Mario, included a lack of communication between the research and clinical worlds.

“It's really important that basic research discoveries are connected to the translation side of things,” he said.

“For a long time, especia l ly in Europe, researchers would just stay in t heir ow n world and were not motivated to interact with the wider medical community. That is starting

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to change but we still need to improve things further.”

Complex communication in immuno-oncology He added that the immunology space in general, and cellular therapy in particular, had its own unique set of obstacles.

“A key hurdle for cellular therapy is that some of these things are too complicated to be easily translatable or applicable to a broad range of people in a cost-effective way,” he said. “But first of all, a deep analysis and understanding of mechanisms is crucial for successful translation in immuno-oncology.

D i s c o ve r i n g a n d u n r av e l l i n g mechanism in the complex interplay of immunology and oncology can be difficult,” said Mario, whose company provides comprehensive research tools to address these challenges, including sample preparation, cell separation, cell culture, and cell analysis, including flow cytometry and imaging.

“Also, the generation of cellular t herapy produc t s is a complex procedure, which involves a lot of different elements. It involves selecting the right cells, it involves culturing the right cells in the right medium and with the right cytokines, and it involves genetic engineering of the cells.

Based on a strong exper tise in immunology and oncology we aim to enable workflow solutions for research as well as clinical translation.”

Embracing opportunities With so many exciting opportunities presenting themselves in immunother-

apy, carving out a clear path to clinic holds huge p otent ia l for both developers and patients.

“We want to make translation as easy as possible and finding the r ight ba lance bet ween risks and oppor tunities.

Sometimes we are too afraid to step into innovation to make progress possible,” said Mario.

Asked where he saw this progress manifesting in the immediate future, Mario said it was a very exciting time.

“Gene-engineered immune cells is a very powerful avenue that has now started to take off with CAR-T cells and I think will grow heavily. TCRengineered T-cells are coming and the genetic engineering of T-cells, especially in solid cancer, is another big topic.”

Embracing these opportunities by moving early research success from basic science into the solid cancer clinical arena is “the next big step” – but it depends on effective translation.

Collaborative approach Mario believes success relies on engendering collaboration: bringing all the different viewpoints, expertise and priorities out of their silos and into one single mission.

“At M i lteny i, we h ave a lon g tradition of intense collaboration with the research community, working in close interaction with researchers on more basic research as well as clinical researchers in different conditions,” he said.

“It means the people who use our technology know their needs, what the crucial points in their applications are and understand the medical needs when it comes to the clinical side of things.”

This approach, he added, led to a deeper understanding of implementation right along the pathway, and, crucially, ensured new treatments made it to the patients who needed them sooner, rather than later.

Byline: Amanda Barrell

Sponsored by

Read more at miltenyibiotec/immunooncology HEALTHAWARENESS.CO.UK 5

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What does immunology need to succeed?

Immunology is at the cutting-edge of our knowledge of how the body works. But how can we create the right environment to allow immunology research to thrive and translate into life-changing impact for patients?

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he f ield of i m mu nolog y i s expanding at a significant rate, spreading its inf luence into many new disciplines and helping us better understand how our bodies function in health and disease.

The Government’s aim to increase spending on research to 2.4% GDP by 2027, highlights immunology as a key player in the life sciences sector. As one of the UK’s research strengths, this growth is only set to continue.

The drive for immunology knowledge and application is thriving and we need to seize this opportunity to think innovatively. How we can create the right environment in terms of infrastructure, investment and skills to realise the benefits for human health? And how can we secure inward investment into the UK from biotech and pharma?

At the British Societ y for Immunology, we are a central force to create that environment. As the largest immunological society in Europe, we are bringing together different players

to galvanise the community, build collaborations and provide the supporting infrastructure to allow the research effort to be stepped up.

Connecting immune research and removing silos One exciting new approach we’re t a k i n g i s v i a C o n n e c t I m mu n e Re s e a rc h, a novel c ol l ab or at ion between four organisations working in the autoimmunity space – JDRF, MS Society, Versus Arthritis and ourselves.

This initiative brings together researchers with different expertise to examine the mechanisms of autoimmunity in a non-condition-specific way. We aim to change the traditional approach to how autoimmune conditions are researched to allow the science to progress faster.

Col laboration – and eschew ing working in disease silos – aims to increase the visibility of autoimmunity in public and scientific debate. We hope to create funding streams to support cross-disease research and bring about

DR DOUG BROWN Chief Executive, British Society for Immunology

positive change to the lives of people living with these conditions.

Collaborating to defeat cancer Another approach we are taking is off the back of the Association of the British Pharmaceutical Industry recently citing immunology as a key research area where there is a skills gap.1 With the recent advent of cancer immunotherapies, there is a lot more we can do to facilitate sk ills and knowledge transfer between the cancer and immunology fields in both medical and research communities.

Our new, g round-break ing collaboration with the National Cancer Research Institute (NCRI) is going to transform how the immunology research community and cancer scientists and clinicians integrate. It will drive new collaborations that address challenges in immunotherapy, as well as advancing understanding of the interaction between the immune system and cancer.

Through several different initiatives, such as training courses and interdisciplinary workshops, we hope to facilitate dialogue between the two communities to speed up discovery in the clinical research space. Improved communication w ill increase the number of cancers that can be targeted through immunotherapy as well as aiding clinician knowledge on recent breakthroughs in our understanding of how the immune system functions in different cancer types.

Enabling research to thrive Immunology is such an exciting field to work in, with a rich pipeline of biological agents now making the transition from bench to bedside. By working with partners and supporting the underlying infrastructure of the sector, the British Society for Immunology hopes to facilitate an environment where new research endeavours can thrive, progress and translate into life-changing impact for patients.

1: Association of British Pharmaceutical Industry 2019 Bridging the skills gap in the biopharmaceutical industry: maintaining the UK’s leading position in the life sciences

Combining vaccines and checkpoint blockades to fight cancer Immunotherapy is a type of cancer treatment that harnesses the body’s own immune system to kill tumours. It has already dramatically improved the outlook for certain types of cancer, particularly in patients who have become resistant to standard treatments, such as chemotherapy.

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ytotoxic T-lymphocytes (or killer T cells) usually detect damaged cells or those infected with viruses, however they can also recognise cancer cells as if they were a foreign body.

They do this by detecting small peptides, which are displayed by MHC class I molecules, that decorate the surface of every cell in the body.

Cancer cells present surface peptides that mark them as foreign Pioneering work by researchers at the Ludwig institute in Brussels in the late 1980’s revealed that cancer cells display three types of surface peptides via the MHC class I that mark them as foreign.

The first are derived from proteins that are only made in cancer cells, the second are derived from proteins that have mutated to drive cancer development, and the third are created by the thou-

6 HEALTHAWARENESS.CO.UK

sands of genetic mutations that occur in individual tumours as they progress.

These proteins essentially flag the cancer cells as foreign, meaning that they can be spotted and targeted by killer T cells.

Potential to develop cancer vaccines Killer T cells can accumulate inside tumours. Although their cytotoxic function is usually inactivated in the tumour microenvironment, the fact that they are present can be used to our advantage; and they can even be reactivated.

Checkpoint blockade immunotherapy, which rejuvenates killer T cells by blocking the inhibitory signals that they receive, is one of the most important revolutions in cancer therapy. Researchers are now excited by the prospect of developing cancer vaccines – another type of immunotherapy that targets antigens expressed on cancer cells – that can be

PROFESSOR TIM ELLIOTT Southampton Cancer Research UK Centre

used in combination with checkpoint blockade immunotherapy.

Protein dynamics is a fascinating area of biochemistry for understanding anti-cancer immunity The focus of my work is understanding how MHC class I molecules select which tumour-derived peptides to present at the cell surface from a vast pool of possible candidates; and how changes in the environment of a growing tumour can influence this process. Our research has led us into a fascinating new area of biochemistry called protein dynamics, which at first seems remote from the business of curing cancer but will, we hope, help us to understand the specificity of anti-cancer immunity.

I molecules are not static entities; they move in a specific way, allowing them to act as immunological “sentinels”. And because there are many different variants of the MHC class I molecule in the human population, they all have slightly different propensities when it comes to selecting cancer peptides.

By collecting this information and building it into computer programmes, we hope to be able to predict exactly which cancer-derived peptides will boost the killer T cells that do the most harm to the tumour, without damaging normal tissue. This will provide a basis for designing better cancer vaccines and may even allow us to select patients who will respond well to checkpoint blockade immunotherapy.

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