̽��ֱ�� of Cambridge - Duncan Jodrell

̽��ֱ��self-defence force awakens

cjb250 — Tue, 04 Jul 2017 16:50:17 +0000

An army of cells constantly patrols within us, attacking anything it recognises as foreign, keeping us safe from invading pathogens. But sometimes things go wrong: the soldiers mistake benign cells for invaders, turning their friendly fire on us and declaring war.

̽��ֱ��consequences are diseases like multiple sclerosis (MS), asthma, inflammatory bowel disease, type 1 diabetes and rheumatoid arthritis – diseases that are increasing at an alarming rate in both the developed and developing worlds.

Cambridge will be ramping up the fight against immune-mediated and inflammatory diseases with the opening next year of the Cambridge Institute of Therapeutic Immunology and Infectious Disease, headed by Professor Ken Smith. ̽��ֱ��Institute will work at the interface between immunity, infection and the microbiome (the microorganisms that live naturally within us). “We’re interested in discovering fundamental mechanisms that can turn the immune system on or off in different contexts, to modify, treat or prevent both inflammatory and infectious diseases,” says Smith.

But while diseases such as Crohn’s and asthma have long been understood to be a consequence of friendly fire, scientists are starting to see this phenomenon give rise to more surprising conditions, particularly in mental health.

In 2009, Professor Belinda Lennox, then at Cambridge and now at Oxford, led a study that showed that 7% of patients with psychoses tested positive for antibodies that attacked a particular receptor in the brain, the NMDA receptor. This blocked a key neurotransmitter, affecting communication between nerve cells and causing the symptoms.

Professor Alasdair Coles from Cambridge’s Department of Clinical Neurosciences is working with Lennox on a trial to identify patients with this particular antibody and reverse its effects. One of their treatments involves harnessing the immune system – weaponising it, one might say – to attack rogue warriors using rituximab, a monoclonal antibody therapy that kills off B-cells, the cells that generate antibodies.

“You can make monoclonal antibodies for experimental purposes against anything you like within a few days,” explains Coles. “In contrast, to come up with a small molecule – the alternative sort of drug – takes a long, long time.”

̽��ֱ��first monoclonal antibody to be made into a drug, created here in Cambridge, is called alemtuzumab. It targets both B- and T-cells and has been used in a variety of autoimmune diseases and cancers. Its biggest use is in MS, where it eliminates the rogue T- and B-cells that attack the protective insulation (myelin sheath) around nerve fibres. Licensed in Europe in 2013 and approved by NICE in 2014, it has now been used in tens of thousands of MS patients.

As well as treating diseases caused by the immune system, antibody therapies are now widely used to treat cancer. And, as Professor Gillian Griffiths, Director of the Cambridge Institute for Medical Research, explains, antibody-producing cells are not the only immune cells that can be weaponised.

“T-cells are also showing great promise,” she says. “They are the body’s serial killers, patrolling, identifying and destroying infected and cancer cells with remarkable precision and efficiency.”

But cancer cells are able to trick T-cells by sending out a ‘don’t kill’ signal. Antibodies that block these signals, which have become known as ‘checkpoint inhibitors’, are proving remarkably successful in cancer therapies. “My lab focuses on what tells a T-cell to kill, and how you make it a really good killer, using imaging and genetic approaches to understand how these cells can be fine-tuned,” Griffiths explains. “This has revealed some novel mechanisms that play key roles in regulating killing.”

A second, more experimental, approach uses souped-up cells known as chimeric antigen receptor (CAR) T-cells programmed to recognise and attack a patient’s tumour.

Neither approach is perfect: antibody therapies can dampen down the entire immune system, causing secondary problems, while CAR T-cell therapies are prohibitively expensive as each CAR T-cell needs to be programmed to suit an individual. But, says Griffiths, “the results to date from both approaches are really rather remarkable”.

One of the problems that’s dogged immunotherapy trials is that T-cells only have a short lifespan. Most of the T-cells transplanted during immunotherapy are gone within three days, nowhere near long enough to defeat the tumour.

This is where Professor Randall Johnson comes in. He’s been working with a molecule (2-hydroxyglutarate), which he says has “become trendy of late”. It’s an ‘oncometabolite’, believed to be responsible for making cells cancerous, which is why pharmaceutical companies are trying to inhibit its action. Johnson has taken the opposite approach.

He’s shown that a slightly different form of the molecule plays a critical role in T-cell function: it can turn them into renewable cells that hang around for a long time and can reactivate to combat cancer. Increasing the levels of this molecule in T-cells makes them stay around longer and be much better at destroying tumours. “Rather than creating killer T-cells that are active from the start, but burn out very quickly, we’re creating an army of cells that can stay quiet for a long time, but will go into action when necessary.”

This counterintuitive approach caught the attention of Apollo Therapeutics, who recognised the enormous promise and has invested in Johnson’s work, which he carried out in mice, to see if it can be applied to humans.

But T-cells face other problems, particularly in pancreatic cancer, explains Professor Duncan Jodrell from the Cancer Research UK Cambridge Institute, which is why immunotherapy against these tumours has so far failed. ̽��ֱ��problem with pancreatic cancer is that ‘islands’ of tumour cells sit in a ‘sea’ of other material, known as stroma. As Jodrell and colleagues have shown, it’s possible for T-cells to get into the stroma, but they go no further. “You can rev up your T-cells, but they just can’t get at the tumour cells.” They are running a study that tries to overcome this immune privilege and allow the T-cells to get to the tumour cells and attack them.

Tim Eisen, Professor of Medical Oncology at Cambridge and Head of the Oncology Translational Medicine Unit at AstraZeneca, believes we can expect great advances in cancer treatment from optimising and, in some cases, combining existing checkpoint inhibitor approaches.

Eisen is working with the Medical Research Council to trial checkpoint inhibitor antibody therapies as a complement – ‘adjuvant’ – to surgery for kidney cancer. Once the kidney is removed, the drug is used to destroy stray tumour cells that have remained behind. But even antibody therapies, which are now widely used within the NHS, are not universally effective and can cause serious complications. “One of the most important things for us to focus on now is which immunotherapeutic drug or particular combination of drugs might be effective in destroying tumour cells and be well tolerated by the patient.”

T-cell therapies – and, in particular, CAR T-cell therapies – are “very exciting, futuristic and experimental,” he says, “but they’re going to take some years to come in as standard therapy.”

̽��ֱ��problem is how to make them cost-effective. “It’s never going to be easier to engineer an individual person’s T-cells than it is to take a drug off the shelf and give it to them,” he says. “ ̽��ֱ��key is going to be whether you can industrialise production. But I’m very optimistic about our ability to re-engineer processes and make it available for people in general.”

We may soon see an era, then, when our immune systems become an unstoppable force for good.

Our immune systems are meant to keep us healthy, but sometimes they turn their fire on us, with devastating results. Immunotherapies can help defend against this ‘friendly fire’ – and even weaponise it in our defence.

T-cells are the body’s serial killers, patrolling, identifying and destroying infected and cancer cells with remarkable precision and efficiency.

Gillian Griffiths

̽��ֱ��moment when a T-cell kills

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Weight loss condition provides insight into failure of cancer immunotherapies

cjb250 — Tue, 08 Nov 2016 17:00:36 +0000

Cancer immunotherapies involve activating a patient’s immune cells to recognise and destroy cancer cells. They have shown great promise in some cancers, but so far have only been effective in a minority of patients with cancer. ̽��ֱ��reasons behind these limitations are not clear.

Now, researchers at the Cancer Research UK Cambridge Institute at the ̽��ֱ�� of Cambridge have found evidence that the mechanism behind a weight loss condition that affects patients with cancer could also be making immunotherapies ineffective. ̽��ֱ��condition, known as cancer cachexia, causes loss of appetite, weight loss and wasting in most patients with cancer towards the end of their lives. However, cachexia often starts to affect patients with certain cancers, such as pancreatic cancer, much earlier in the course of their disease.

In research published today in the journal Cell Metabolism, the scientists have shown in mice that even at the early stages of cancer development, before cachexia is apparent, a protein released by the cancer changes the way the body, in particular the liver, processes its own nutrient stores.

“ ̽��ֱ��consequences of this alteration are revealed at times of reduced food intake, where this messaging protein renders the liver incapable of generating sources of energy that the rest of the body can use,” explains Thomas Flint, an MB/PhD student from the ̽��ֱ�� of Cambridge School of Clinical Medicine and co-first author of the study. “This inability to generate energy sources triggers a second messaging process in the body – a hormonal response – that suppresses the immune cell reaction to cancers, and causes failure of anti-cancer immunotherapies.”

“Cancer immunotherapy might completely transform how we treat cancer in the future – if we can make it work for more patients,” says Dr Tobias Janowitz, Medical Oncologist and Academic Lecturer at the Department of Oncology at the ̽��ֱ�� of Cambridge and co-first author. “Our work suggests that a combination therapy that either involves correction of the metabolic abnormalities, or that targets the resulting hormonal response, may protect the patient’s immune system and help make effective immunotherapy a reality for more patients.”

̽��ֱ��next step for the team is to see how this discovery might be translated for the benefit of patients with cancer.

“If the phenomenon that we’ve described helps us to divide patients into likely responders and non-responders to immunotherapy, then we can use those findings in early stage clinical trials to get better information on the use of new immunotherapies,” says Professor Duncan Jodrell, director of the Early Phase Trials Team at the Cambridge Cancer Centre and co-author of the study.

“We need to do much more work in order to transform these results into safe, effective therapies for patients, however,” adds Professor Douglas Fearon, Emeritus Sheila Joan Smith Professor of Immunology at the ̽��ֱ�� of Cambridge and the senior author, who is now also working at Cold Spring Harbor Laboratory and Weill Cornell Medical College. “Even so, the results raise the distinct possibility of future cancer therapies that are designed to target how the patient’s own body responds to cancer, with simultaneous benefit for reducing weight loss and boosting immunotherapy.”

̽��ֱ��research was largely funded by Cancer Research UK, the Lustgarten Foundation, the Wellcome Trust and the Rosetrees Trust.

Nell Barrie, senior science information manager at Cancer Research UK, said: "Understanding the complicated biological processes at the heart of cancer is crucial for tackling the disease - and this study sheds light on why many cancer patients suffer from both loss of weight and appetite, and how their immune systems are affected by this process. Although this research is in its early stages, it has the potential to help make a difference on both fronts - helping treat weight loss and also improving treatments that boost the power of the immune system to destroy cancer cells."

Reference
Flint, TR et al. Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity. Cell Metabolism; 8 Nov 2016; DOI: 10.1016/j.cmet.2016.10.010

A weight loss condition that affects patients with cancer has provided clues as to why cancer immunotherapy – a new approach to treating cancer by boosting a patient’s immune system – may fail in a substantial number of patients.

Cancer immunotherapy might completely transform how we treat cancer in the future – if we can make it work for more patients

Tobias Janowitz

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̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Smart testing for smart drugs

bjb42 — Mon, 04 Jan 2010 14:29:04 +0000

Discovering and evaluating anticancer drugs is a billion dollar business. Much effort is put into the discovery of novel drug targets and then elegant chemistry approaches are used to design and synthesise new therapeutics. ‘With the increasing biological understanding of cancer, an increasing repertoire of potential targets has been identified,’ explained Professor Duncan Jodrell, at the Cancer Research UK Cambridge Research Institute (CRI). ‘But, in the past, time and money have been wasted performing large-scale clinical trials on compounds that end up not having a significant impact on cancer. With many more potential drugs, we need to avoid this happening in the future’. Therefore, a major question is which drugs should be progressed to clinical trials?

Professor Jodrell and Dr David Tuveson, also at the CRI, believe that the answer lies in re-designing the way that preclinical studies are performed and in developing more-relevant animal models of the human disease. Essentially, smart drugs deserve smart evaluation. ‘ ̽��ֱ��development of anticancer drugs is therefore likely to have the highest impact when performed at centres that are world-leading in preclinical cancer models, novel therapeutics, molecular imaging and ‘science-led’ clinical application of novel therapies in patients,’ explained Dr Tuveson. ‘All of these components are coming together at the CRI and laboratories close by.’

GEMs of discovery

For many years, mouse models have been an invaluable resource to understand the mechanisms that underpin cancer in human patients. These models have become increasingly sophisticated, starting with xenograft models, in which part of a tumour removed from a patient is transplanted into mice, through to the latest genetically modified mouse (GEM) models, which carry the mutations that have been associated with particular human cancers.

‘One bottleneck for bringing new therapies into the clinic is the extent to which preclinical testing quickly and accurately predicts how well a drug will perform once it enters clinical trials in patients,’ explained Dr Tuveson, who leads the Tumour Modelling and Experimental Medicine group. ‘Our goal is to improve the ability to discriminate between drugs that will have significant patient benefits and those that won’t.’

Dr Tuveson’s particular focus has been on pancreatic cancer and melanoma – two of the most difficult cancers to treat. Despite the fact that we now know which gene is predominantly responsible for each of these types of cancers, patients have a poor prognosis as few treatments are available and many tumours do not respond to them.

Recently, his group discovered a new mechanism that might explain why pancreatic cancer is often resistant to gemcitabine, a commonly used anticancer treatment. Working with colleagues at Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (Addenbrooke’s) and laboratories in the USA and Europe, the scientists found that resistance to chemotherapy is the result of the pancreatic tumours having a poor network of blood vessels, which makes it harder for drugs to reach the tumour. This result, published a few months ago in Science, may also explain why anticancer drugs targeted at blood vessels (which some tumours have in abundance) don’t work for pancreatic cancer.

‘Working out why some tumours show a disappointing response to chemotherapeutic drugs has enabled us to look at what can be done to overcome this therapeutic intractability,’ said

Dr Tuveson. ‘If the door has been closed to therapy, perhaps we can find a way of reopening it?’ Early studies have shown that a compound called IPI-926, created by Infinity Pharmaceuticals, reduces the amount of tissue surrounding the tumour, allowing greater access for gemcitabine.

Dr Tuveson is also working with colleagues at the Wellcome Trust Sanger Institute to identify genes and pathways that influence cancer development – information that will be used to develop new models that mimic human cancers. ̽��ֱ��proximity in Cambridge of several drug development programmes – such as the Cambridge Molecular Therapeutics Programme at the Hutchison/Medical Research Council (MRC) Research Centre and groups within the Departments of Chemistry and Biochemistry – will offer broad access to novel therapeutic classes for this work.

Entering a new phase

‘Although the results are extremely promising,’ said Dr Tuveson, ‘these are early days and we need to show that this approach is safe to use in humans before we can consider adding the new compound to cancer treatments.’ To do this, Dr Tuveson is working with Professor Jodrell, who leads the Cancer Research UK Pharmacology and Drug Development Group at the CRI and a closely associated Early Phase Trials Team based in Addenbrooke’s Hospital.

Professor Jodrell is interested in what anticancer drugs do to the body (pharmacodynamics) and how the body handles the drug (pharmacokinetics). ‘These are important determinants of successful therapy since the measurements provide information on whether the drug is hitting the right target. We also learn how long the drug hangs around to do this before it’s metabolised or eliminated.’

An oncology clinic for pancreatic cancer patients is being developed at Addenbrooke’s Hospital and early phase clinical trials are performed in the Wellcome Trust Clinical Research Facility on the same campus. This allows the preclinical studies initiated in CRI laboratories to be translated into clinical benefits for patients. Trials will be available for patients with both early and advanced disease. ‘We will be looking for biomarkers that can identify which tumours will respond to a particular treatment, as well as markers that demonstrate early that the treatment is working,’ explained Professor Jodrell. ‘ ̽��ֱ��goal is to identify which patients will benefit from drugs, and to get more information at an earlier stage to inform those ‘go/no go’ decisions for progressing a drug through to later-phase clinical trials.’ For both the preclinical and clinical studies, novel imaging techniques devised by Professor Kevin Brindle and Professor John Griffiths at the CRI may provide instantaneous assessment of response to treatment. In patients, these non-invasive imaging tools will hopefully maximise the information accrued, yet avoid the discomfort for patients of undergoing serial biopsies to obtain tumour tissue.

Information from the preclinical models of pancreatic disease developed by Dr Tuveson will soon be integrated into clinical trials. A clinical trial protocol will commence in Cambridge in early 2010 to test novel combinations of gemcitabine and other drugs. Collaboration with Dr Adrian Mander, leader of the MRC Biostatistics Unit Hub in Trials Methodology Research in Cambridge, is providing statistical approaches to maximise the information derived from the trials.

Anticancer cocktails

̽��ֱ��unique mirroring arrangement between preclinical models and clinical trials that is being created in Cambridge holds great promise for moving towards individualised therapy for cancer patients. Novel and established drugs can be tested quickly and effectively to work out the appropriate combination that will overcome lack of response to treatment. ‘It’s now possible to imagine the day,’ said Professor Jodrell, ‘when each patient is treated with a personalised cocktail of drugs that takes account of the specific attributes of their cancer.’

For more information, please contact Dr David Tuveson (david.tuveson@cancer.org.uk) and Professor Duncan Jodrell (duncan.jodrell@cancer.org.uk) at the Cancer Research UK Cambridge Research Institute/Li Ka Shing Centre.

Can better decisions be made about which anticancer drugs to progress to clinical trials?

Kenneth olive, Stefanie Reichelt and Michael Jacobetz

Pancreatic Tumour

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