tag:theconversation.com,2011:/id/topics/immune-therapy-4392/articlesImmune therapy – The Conversation2019-06-19T10:57:06Ztag:theconversation.com,2011:article/1180202019-06-19T10:57:06Z2019-06-19T10:57:06ZNew research gives hope in the fight against pancreatic cancer<figure><img src="https://images.theconversation.com/files/277571/original/file-20190603-69071-kvx656.jpg?ixlib=rb-1.1.0&rect=0%2C31%2C7000%2C4516&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>Pancreatic ductal adenocarcinoma (PDAC), the most common form of <a href="https://pancreapedia.org/reviews/pancreatic-ductal-adenocarcinoma">pancreatic cancer</a>, is the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396775/">third most common cause of death from cancer</a> in the United States and the fifth most common in the United Kingdom. Deaths from PDAC outnumber those from breast cancer despite the significant <a href="http://publications.iarc.fr/Non-Series-Publications/World-Cancer-Reports/World-Cancer-Report-2014">difference in incidence rates</a>.</p>
<p>Late diagnosis and ineffective treatments are the most important reasons for these bleak statistics.</p>
<p>PDAC is an aggressive and difficult malignancy to treat. Until now, the only chance for cure is the complete surgical removing of the tumor. Unfortunately, because PDAC is usually asymptomatic, by the time it is diagnosed 80% to 90% of patients have disease that is surgically incurable. PDAC thus remains one of the main biomedical challenges today due to its low survival rate – just <a href="http://publications.iarc.fr/Non-Series-Publications/World-Cancer-Reports/World-Cancer-Report-2014">5% of patients are still alive five years after diagnosis</a>.</p>
<p>However, in recent decades a number of studies have shed light on the molecular mechanisms responsible for the initiation and progression of PDAC. Our <a href="https://www.cell.com/cancer-cell/fulltext/S1535-6108%2819%2930111-4">recent research</a> has shown that progress toward a cure is possible.</p>
<h2>Ineffective treatments</h2>
<p>The molecular mechanisms responsible for pancreatic cancer are complex. This is why recent advances in <a href="https://theconversation.com/the-promise-of-personalized-medicine-is-not-for-everyone-100997">personalized medicine</a> and <a href="https://theconversation.com/2018-nobel-prize-in-physiology-or-medicine-a-turning-point-in-the-war-on-cancer-104191">immunotherapy</a> (which helps the immune system fight cancer) have failed to improve the treatment of pancreatic cancer. This is mainly due to two characteristics:</p>
<ul>
<li><p>95% of these tumors are caused by mutations in KRAS oncogenes. Oncogenes are genes that, once mutated, are capable of inducing the transformation of a normal cell into a cancerous cell. KRAS is a gene that <a href="https://www.cancer.gov/news-events/cancer-currents-blog/2015/turning-off-broken-switch">acts as an on/off switch</a>. Normally, KRAS controls cell proliferation. When it is mutated, however, the cells start to grow uncontrollably and proliferate – a hallmark of cancer cells. So far, KRAS oncogenes have not been able to be targeted by drugs.</p></li>
<li><p>PDACs are surrounded by abundant fibrous connective tissue that <a href="https://www.medicinenet.com/script/main/art.asp?articlekey=7458">grows</a> around some tumor types. In the case of PDAC, this tissue forms a barrier that prevents cells that recognize and attack tumor cells, called <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cytotoxic-t-cell">cytotoxic T lymphocytes</a>, from reaching the inside of the tumor mass and killing its cells. This renders immunotherapy treatments useless.</p></li>
</ul>
<p>For these reasons, PDAC continues to be treated with drugs that destroy cancerous cells but can also destroy healthy ones. Options include <a href="https://en.wikipedia.org/wiki/Gemcitabine">Demcitabine</a>, approved in 1997, and Nab-paclitaxel, a new <a href="https://en.wikipedia.org/wiki/Paclitaxel">paclitaxel-based formulation</a>. Even if such a treatment is an option, it typically only extends the patients’ lives a few weeks, a marginal improvement at best.</p>
<p>In recent years, however, a number of studies have shed light regarding the molecular mechanisms responsible for the initiation and progression of PDAC.</p>
<p>Today we know that most of these tumors are caused by mutations in the KRAS oncogene. They lead to benign alterations that cause additional mutations in a range of <a href="https://www.cancer.org/cancer/cancer-causes/genetics/genes-and-cancer/oncogenes-tumor-suppressor-genes.html">tumor-suppressor genes</a>, which usually repair DNA mistakes, slow down cellular division or tell cells when to die. Mutated cells can grow out of control, and in this context progress to malignant PDAC.</p>
<p>While this process is relatively well known, it has not had an immediate impact on the development of new and more effective treatments.</p>
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Leer más:
<a href="https://theconversation.com/2018-nobel-prize-in-physiology-or-medicine-a-turning-point-in-the-war-on-cancer-104191">2018 Nobel Prize in Physiology or Medicine: a turning point in the war on cancer</a>
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<h2>In search of new strategies</h2>
<p>Multiple strategies are currently being studied in an attempt to inhibit the growth of these tumors by blocking the growth of either the tumor cells or their surrounding “shielding” connective tissue. <a href="https://www.axa-research.org/fr/projet/mariano-barbacid">In our laboratory</a>, we focused on blocking the signaling pathways that mediate the oncogenic activity of the initiating KRAS oncogenes.</p>
<p>A decade ago, our lab decided to use genetically engineered mouse-tumor models capable of reproducing the natural history of human PDAC. We did this in order to analyze the therapeutic potential of the main components of the KRAS signaling pathways. These studies have unveiled the reason why the drugs tested so far have intolerable toxic effects, with mice dying within several weeks: they target some proteins that are essential for the dynamic state of equilibrium that is the condition of optimal functioning of the cells. This is called <a href="https://en.wikipedia.org/wiki/Homeostasis">normal homeostasis</a>.</p>
<p>These crucial proteins are mainly <a href="https://en.wikipedia.org/wiki/Kinase">kinases</a>, enzymes that are able to modify how other molecules function. They play a critical and complex role in regulating cellular signaling and orchestrate processes such as hormone response and cell division. These results might explain why the KRAS-signaling inhibitors tested so far have <a href="https://jamanetwork.com/journals/jama/issue/317/18">failed in clinical trials</a>. On the other hand, the removal of other signaling kinases did not have toxic side effects, but also had no impact on tumor development.</p>
<p>Of the more than 15 kinases involved in the transmission of signals from the KRAS oncogene, only three displayed significant therapeutic benefits without causing unacceptable side effects. These are: <a href="https://en.wikipedia.org/wiki/RAF_kinase">RAF1</a>, the <a href="https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor">epidermal growth factor receptor</a> (EGFR) and <a href="https://en.wikipedia.org/wiki/Cyclin-dependent_kinase_4">CDK4</a>.</p>
<h2>It works! (in mice)</h2>
<p>In initial studies, we observed that the elimination (via genetic manipulation) of the expression of some of these three kinases prevented the onset of PDAC caused by the KRAS oncogene. However, its elimination in animals with advanced tumors had no significant therapeutic effects. These results caused us to question whether it would be possible to eliminate more than one kinase simultaneously without increasing the toxic effects.</p>
<p>As described in our recent work published in the journal <a href="https://www.sciencedirect.com/science/article/abs/pii/S1535610819301114"><em>Cancer Cell</em></a>, the elimination of RAF1 and EGFR expression induced the complete regression of advanced PDACs in 50% of the mice. <a href="https://www.ncbi.nlm.nih.gov/pubmed/30975481">We are currently studying</a> whether we can increase this by also eliminating CDK4.</p>
<p>The analysis of the pancreas of animals in which we were no longer able to observe tumors by imaging techniques revealed the complete absence of lesions in two of them. Two mice showed some abnormal ducts, probably residual scarring from the tumor. The others had tumor micro-masses of one-thousandth the size of the original tumor. The study of these revealed the presence of tumor cells, in which the expression of the two targets, EGFR and RAF1, had not been completely eliminated, a common technical problem in this type of study.</p>
<p>It is significant that these results were observed not only in mice. The inhibition of the expression of these two proteins in cells derived from nine out of ten human PDACs were also capable of blocking their proliferation <em>in vivo</em> when transplanted into immunosuppressed mice as well as <em>in vitro</em> cultures.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/278680/original/file-20190610-52741-btpg9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/278680/original/file-20190610-52741-btpg9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/278680/original/file-20190610-52741-btpg9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/278680/original/file-20190610-52741-btpg9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/278680/original/file-20190610-52741-btpg9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/278680/original/file-20190610-52741-btpg9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/278680/original/file-20190610-52741-btpg9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The elimination of RAF1 and EGFR expression induced the complete regression of advanced PDACs in half of the mice.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Lab_mouse_mg_3276.jpg">Rama/Wikimedia</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<h2>What now?</h2>
<p>While these results have only been observed in a subset of mice for now, their importance lies in the fact that it is the first time that it has been possible to completely eliminate advanced PDAC tumors by eliminating a pharmacologically directed target.</p>
<p>These observations are clearly important for the development of treatments based on the inhibition of RAF1 and EGFR, but they only represent a first step on a long, hard road ahead.</p>
<p>First, it is important to identify the differences between the PDACs that respond to the combined elimination of RAF1 and EGFR and those that are resistant. As described in our work, the analysis of these two tumor types revealed that they are not active in the same way – more than 2,000 genes are expressed differently.</p>
<p>Identifying additional targets in resistant tumors that do not increase treatment toxicity is not going to be an easy task.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/wUJDAeU7J7E?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Mariano Barbacid speaks about precision medicine and cancer, Bose Memorial conference, 2018.</span></figcaption>
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<p>To continue our tests with genetically engineered mice, the immediate but no less difficult task is the development of specific RAF1 <a href="https://medical-dictionary.thefreedictionary.com/inhibitor">inhibitors</a>. Indeed, we only currently have potent drugs against the second target, EGFR. In principle, there are four possible approaches:</p>
<ul>
<li><p>Generate selective inhibitors for its kinase activity.</p></li>
<li><p>Generate inhibitors for its binding to the KRAS oncogene.</p></li>
<li><p>Generate inhibitors for its interaction with effector targets that transmit oncogenic signaling mediated by RAF1.</p></li>
<li><p>Degrade the RAF1 protein with drugs.</p></li>
</ul>
<p>Designing inhibitors of the RAF1 kinase activity would seem to be the most affordable option, given the experience of the pharmaceutical industry in <a href="https://www.ncbi.nlm.nih.gov/pubmed/26822576">designing this molecule type</a>.</p>
<p>The problem resides in the fact that there are two other kinases of the same family, ARAF and BRAF, whose catalytic centers (the “active core” of the enzymes) are nearly identical. RAF1 kinase inhibitors are also targeting these other kinases, which causes collateral damage. The ones tested to date have caused high toxicities and the clinical trials had to be stopped.</p>
<p>Continuing to develop effective molecules that are capable of blocking RAF1 activity in patients with PDAC will not be easy. It will surely take more time than we hope, but at least a road map has already been outlined that shows us how to keep moving forward.</p>
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<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/202296/original/file-20180117-53314-hzk3rx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/202296/original/file-20180117-53314-hzk3rx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=121&fit=crop&dpr=1 600w, https://images.theconversation.com/files/202296/original/file-20180117-53314-hzk3rx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=121&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/202296/original/file-20180117-53314-hzk3rx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=121&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/202296/original/file-20180117-53314-hzk3rx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=152&fit=crop&dpr=1 754w, https://images.theconversation.com/files/202296/original/file-20180117-53314-hzk3rx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=152&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/202296/original/file-20180117-53314-hzk3rx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=152&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<p><em>Created in 2007 to help accelerate and share scientific knowledge on key societal issues, the AXA Research Fund has been supporting nearly 600 projects around the world conducted by researchers from 54 countries. To learn more about this AXA Research Fund project, please visit the <a href="https://www.axa-research.org/en/project/mariano-barbacid">dedicated page</a>.</em></p>
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<p><em>This article was translated from the original Spanish by Sara Crespo, <a href="https://www.calamoycran.com/">Calamo & Cran</a>.</em></p><img src="https://counter.theconversation.com/content/118020/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The grants received by Mariano Barbacid to carry out this work are cited in the related article published in the journal Cancer Cell. In addition, he owns shares in pharmaceutical companies, and also holds an endowed Chair in the AXA Research Fund.</span></em></p>Pancreatic cancer currently has one of the least optimistic prognosis, with just 5% of patients surviving five years after diagnosis. A recent study opens a door to hope.Mariano Barbacid, profesor e investigador AXA-CNIO de Oncología Molecular, Centro Nacional de Investigaciones Oncológicas CNIOLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1112502019-04-30T02:29:20Z2019-04-30T02:29:20ZExplainer: what is Sjögren’s syndrome, the condition Venus Williams lives with?<p>Sjögren’s syndrome hit the headlines when US tennis player Venus Williams declared she was <a href="https://www.theguardian.com/sport/blog/2017/jul/17/venus-williams-longevity-diet-wimbledon-tennis">suffering from it</a>.</p>
<p>What is Sjögren’s syndrome? How do you pronounce it anyway? And is there a cure?</p>
<h2>What is it?</h2>
<p><a href="https://www.mayoclinic.org/diseases-conditions/sjogrens-syndrome/symptoms-causes/syc-20353216">Sjögren’s syndrome</a>, pronounced “Showgren’s syndrome”, is what doctors call a chronic systemic autoimmune disease. It’s when the body’s immune system mistakenly attacks itself, leading to healthy tissues being destroyed. It’s chronic because it lasts for a long time, and systemic as it affects different organs.</p>
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Read more:
<a href="https://theconversation.com/explainer-what-are-autoimmune-diseases-22577">Explainer: what are autoimmune diseases?</a>
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<p>It can occur on its own, when it’s known as primary Sjögren’s syndrome, or with another autoimmune condition, such as lupus, rheumatoid arthritis, or systemic sclerosis, and is then called secondary or associated Sjögren’s syndrome. Like most autoimmune diseases, there is no cure.</p>
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<h2>What are the symptoms?</h2>
<p>The most common symptoms arise when immune cells (lymphocytes) attack the body’s own saliva and tear glands. This leads to the body producing fewer tears and less saliva (the so-called sicca syndrome).</p>
<p>Fewer tears leads to dry eyes (keratoconjunctivitis sicca), when the eyes feel gritty and like there’s something lodged there. Eyes also get tired after a lot of reading. Less saliva leads to a dry mouth (xerostomia). The mouth often feels uncomfortable or stings, and people have difficulty chewing and swallowing food.</p>
<p>These symptoms of dryness often also affect other parts of the body such as the nose, upper airways, vagina, and skin.</p>
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Read more:
<a href="https://theconversation.com/explainer-what-is-the-immune-system-19240">Explainer: what is the immune system?</a>
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<p>Fatigue, and muscle and joint pains occur in more than <a href="https://www.nejm.org/doi/full/10.1056/NEJMcp1702514?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed">80% of people</a> with the syndrome, leading to reduced quality of life.</p>
<p>In <a href="https://www.nejm.org/doi/full/10.1056/NEJMcp1702514?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed">30-40% of people</a> with primary Sjögren’s syndrome, other parts of the body are also affected, such as the skin, joints, brain, nerves, lymph nodes, kidneys, heart, and lungs. </p>
<p>There is also a risk of developing <a href="https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/what-is-non-hodgkin-lymphoma.html">non‐Hodgkin lymphoma</a>, that is <a href="https://ard.bmj.com/content/73/6/1151">roughly 14 times higher than in the general population</a>.</p>
<h2>Who is affected?</h2>
<p>Sjögren’s syndrome is one of the most common autoimmune illnesses and the primary form affects about <a href="https://www.nejm.org/doi/full/10.1056/NEJMcp1702514?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed">0.3-1.0 per 1,000 people</a>. </p>
<p>According to the Australian Sjögren’s Syndrome Association website, <a href="http://www.sjogrens.org.au/">up to 0.5% of Australians have the condition</a>, considerably more than the international figures.</p>
<p>However, this figure needs to be confirmed in a prospective epidemiological study, which has yet to be done.</p>
<p>Setting up an Australian national registry would be useful in determining whether the syndrome really is more common in Australians, and for gaining clues about what might cause this condition.</p>
<p>Nine times as many women <a href="https://www.sciencedirect.com/science/article/pii/S1521694216300134?via%3Dihub">are affected</a> as men, and the syndrome is most common in 50-60 year-olds, although children and elderly people can also be affected.</p>
<h2>It’s tricky to diagnose</h2>
<p>This condition is as challenging to diagnose as it is to manage. General symptoms, such as unexplained fever, involuntary weight loss, pain, fatigue, and even dryness, are not specific to this illness, and can delay the diagnosis for years. </p>
<p>Inflammation of the muscles, joints, skin, nervous system, kidneys or lungs – which may lead to organ failure – can also mislead, as this can mimic other diseases such as rheumatoid arthritis, lupus or multiple sclerosis. </p>
<p>It is also important to distinguish primary Sjögren’s syndrome from non-autoimmune conditions such as perimenopause, endocrine disorders, or fibromyalgia, which do not require monitoring or treatment of organs affected by the condition. </p>
<p>Finally, defining whether it is a primary or secondary disease is not always easy.</p>
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Read more:
<a href="https://theconversation.com/hidden-and-unexplained-feeling-the-pain-of-fibromyalgia-48319">Hidden and unexplained: feeling the pain of fibromyalgia</a>
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<p>Primary Sjögren’s syndrome should be suspected in someone with dryness of the mouth and eyes, joint pain and/or fatigue, with or without symptoms of systemic (other organ) complications.</p>
<p>Your doctor will perform a detailed clinical examination, and run non-invasive tests to measure mouth and eye dryness, in consultation with a rheumatologist.</p>
<p>You will also have a specific blood test to confirm the autoimmune disease, and if that is not conclusive you may need a biopsy (a small sample) of the minor salivary gland. This is a minor dental procedure performed under local anaesthetic. It can confirm primary Sjögren’s syndrome and also exclude other diseases that mimic it and need different therapy. </p>
<p>Researchers are looking into whether using <a href="https://onlinelibrary.wiley.com/doi/abs/10.1111/1756-185X.13492">simple ultrasound techniques</a> can help with the difficult task of diagnosis.</p>
<h2>Can we treat it?</h2>
<p>As there is no cure, the best we can do is to manage the symptoms. But the few approved treatment options make this illness extremely challenging to manage. </p>
<p>Fatigue is difficult to treat. Other conditions that cause fatigue such as hypothyroidism and obstructive sleep apnoea need to be ruled out, and patients need to learn how to pace themselves within their limitations, while exercising and keeping as fit as possible.</p>
<p>Artificial tears (eye drops) help lubricate dry eyes and patients need to keep eyelids free from infection. For dental health, regular checkups and fluoride treatment are recommended, as are using sugar-free chewing gum or lozenges to stimulate saliva production.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/270340/original/file-20190423-15194-pi20d1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/270340/original/file-20190423-15194-pi20d1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/270340/original/file-20190423-15194-pi20d1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/270340/original/file-20190423-15194-pi20d1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/270340/original/file-20190423-15194-pi20d1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/270340/original/file-20190423-15194-pi20d1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/270340/original/file-20190423-15194-pi20d1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/270340/original/file-20190423-15194-pi20d1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Special eye drops that mimic tears help to lubricate dry eyes.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/552942619?src=Ku4TgurtALlEVXcf1ebFwg-1-0&size=medium_jpg">from www.shutterstock.com</a></span>
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<p>Chemical stimulation using <a href="https://pubchem.ncbi.nlm.nih.gov/compound/pilocarpine">pilocarpine</a> or <a href="https://www.drugbank.ca/drugs/DB00185">cevimeline</a> (the latter not available in Australia) can stimulate saliva and tear production. </p>
<p>Topical cyclosporine can also be used to treat eye dryness, under supervision of an ophthalmologist, and eye drops made from an extract of the patient’s blood can, in extreme cases, be useful. </p>
<p>Systemic (bodily) symptoms can be treated with glucocorticoids, hydroxychloroquine, or immunosuppressants such as mycophenolate mofetil, rituximab, cyclosporine, azathioprine, methotrexate or leflunomide.</p>
<p>However, none of these drugs used to treat the systemic symptoms have been proven to be effective in clinical trials in treating patients with primary Sjögren’s syndrome; their use is “off-label”, based on how we treat other autoimmune diseases such as lupus.</p>
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Read more:
<a href="https://theconversation.com/explainer-why-are-off-label-medicines-prescribed-44783">Explainer: why are off-label medicines prescribed?</a>
</strong>
</em>
</p>
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<h2>Looking to the future</h2>
<p>Several new treatments for primary Sjögren’s syndrome are being trialled for their safety and efficacy. If approved, they will allow therapy to be tailored to the individual and should lead to an improved quality of life.</p>
<p>Their aim is to stop the progression of the disease, halt the autoimmune process, and help reduce the use of treatments with strong side-effects, such as glucocorticoids and immunosuppressants.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-how-do-drugs-get-from-the-point-of-discovery-to-the-pharmacy-shelf-78915">Explainer: how do drugs get from the point of discovery to the pharmacy shelf?</a>
</strong>
</em>
</p>
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<p>Drugs in trials or soon to be tested include:</p>
<ul>
<li><p>belimumab (promising results from a recent <a href="https://ard.bmj.com/content/74/3/526.long">phase 2 clinical trial</a>, which targets a molecule called <a href="https://www.nature.com/articles/nrrheum.2014.33">BAFF</a>, and which has recently been approved for use in people with lupus)</p></li>
<li><p>belimumab alone or with rituximab, in a new <a href="https://clinicaltrials.gov/ct2/show/NCT02631538">phase 2 clinical trial</a>, and</p></li>
<li><p>several other biological agents that target different steps in the body’s immune response, largely by interfering with the work of key enzymes or receptors.</p></li>
</ul>
<p>Without knowing the precise symptoms Venus Williams lives with, her success and achievements – <a href="http://www.tennis.com/player/406/venus-williams/">still competing with the world’s best tennis players</a> at the age of 38 – is more than impressive. Her fighting spirit, always with a positive attitude, drives hope for other people with Sjögren’s syndrome.</p><img src="https://counter.theconversation.com/content/111250/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Fabien B. Vincent receives funding from the Rebecca L. Cooper Medical Research Foundation. </span></em></p><p class="fine-print"><em><span>Maureen Rischmueller receives funding for consultancy from BMS, CSL and Behring, and for clinical Trials from BMS.</span></em></p>Sjögren’s syndrome has no cure. Here’s how it affects the body and what the future might bring for people with this challenging autoimmune disease.Fabien B. Vincent, Research Fellow; Rheumatology Research Group, Centre for Inflammatory Diseases, Monash UniversityMaureen Rischmueller, Rheumatologist and Associate Professor, Discipline of Medicine, University of AdelaideLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/409442015-07-28T10:20:27Z2015-07-28T10:20:27ZFour challenges we have to crack before immune therapy can revolutionize how we fight cancer<figure><img src="https://images.theconversation.com/files/89822/original/image-20150727-7671-11i949l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Attack.</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-133427873/stock-photo--d-rendered-illustration-of-leukocytes-attacking-a-cancer-cell.html?src=DiEecaBguw-Np8gGVEU0Vw-1-50">Cancer cells and leukocytes via www.shutterstock.com.</a></span></figcaption></figure><p>Most of us know about the conventional treatment of cancer: surgery to remove tumors, chemotherapy and radiation. But within the last five years, a new class of drugs that use our immune systems to fight cancer are gaining traction in cancer treatment. This is called “immunotherapy.” Instead of killing cancer cells with radiation or chemotherapy, immunotherapy mobilizes the immune system to fight against cancer much like it does against bacteria and viruses. </p>
<p>For a training immunologist like myself, immune therapies have opened new doors to understanding and treating cancers. In the future, immunotherapy could mean a personalized treatment, entirely tailored to an individual. As exciting as that sounds, we still have plenty of work to do, as there remains a lot we don’t know about the immune system. Here are some of the challenges we need to overcome to create these personalized treatments.</p>
<h2>Challenge #1: Tumors don’t want the immune system to know they are tumors</h2>
<p>In the late 1980s, researchers started to wonder if the immune system could fight tumors the same way it fought foreign invaders. Studies in <a href="http://dx.doi.org/10.1126/science.3489291">mice</a> and in <a href="http://dx.doi.org/10.1056/NEJM198812223192527">humans</a> showed that when immune cells were extracted from a body, reprogrammed and transferred back into the same body, they caused tumors to temporarily shrink, giving first indications of immunotherapy at work.</p>
<p>In turns out that tumors are pretty vicious in avoiding the immune system. In the 1990s, researchers discovered that tumors can actively put “<a href="https://theconversation.com/immunotherapy-drugs-could-herald-new-era-in-cancer-treatment-39264">brakes</a>” on the body’s immune system to evade <a href="http://dx.doi.org/10.1016/1074-7613(94)90071-X">detection</a> by T-cells, a special kind of immune cell. T-cells search for signs of infection within cells by looking for specific protein codes on the cell surface. When T-cells decide that protein codes displayed on a cell don’t look like they belong to normal cells, they attack these abnormal cells and kill them (as shown in this fantastic video). </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/cJU7ZaWe5-o?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Cytotoxic (Killer) T-cells in action destroying a cancer cell.</span></figcaption>
</figure>
<p>Tumors can block T-cells from recognizing these protein codes. By doing this, tumors essentially go into stealth mode, flying under the radar of immune detection. </p>
<p>We’ve figured this challenge out – sort of. Extensive research on the T-cell brakes eventually led to drugs that <a href="http://dx.doi.org/10.1126/science.271.5256.1734">block</a> the effects of these brakes – allowing the immune system to detect and attack tumors that would otherwise be invisible to it – and present-day cancer immunotherapy was born.</p>
<h2>Challenge #2: Immunotherapy drugs are highly effective, but not in everyone</h2>
<p>Today there are three drugs approved as immune therapies – Ipilumimab, Nivolumab and Pembrolizumab. All three drugs act by releasing the T-cell brakes in different ways, freeing T-cells to look for the small protein codes characteristic of tumor cells.</p>
<p>These drugs have provided long-term remissions in patients with metastatic relapses in cancers such as melanoma and lung cancer. This means that patients whose cancers came back after an initial chemotherapy treatment (often a 3-month death sentence) remarkably survived, in some cases for several years, after their T-cells were rebooted to attack cancer. Very few conventional treatments can offer a comparable second chance after relapse.</p>
<p>But there is a problem: these drugs do not work for everyone. They are approved only to treat melanoma and certain types of lung cancer, and even in these cancers, these drugs only work in some patients. For instance, in about 20% of people with metastatic melanoma, Ipilimumab can <a href="http://dx.doi.org/10.1200/JCO.2014.56.6018">double</a> the long-term survival. For the other 80%, the drug is much less effective. </p>
<p>Scientists say that part of the reason why immunotherapy drugs can be amazingly effective in some patients, and much less effective is others, boils down to differences in our DNA. </p>
<p>Although we share 99.9% of our DNA with each other, there is massive variation from one individual to the next, partly because of our genetics and partly due to the environment. This variation extends to our tumors and our <a href="https://med.stanford.edu/news/all-news/2015/01/environment-not-genes-plays-starring-role-in-immune-variation.html">immune system</a>. Because of this genetic variation that makes us who we are, our immune systems, and thus our cancers, have their own life story. </p>
<p>To try to solve this problem, researchers are trying to understand the <a href="http://dx.doi.org/10.1056/NEJMoa1406498">genetic basis of clinical response to immunotherapies</a>, and developing techniques to identify whether a patient who walks into the clinic with cancer will benefit from these drugs before going under treatment. </p>
<h2>Challenge #3: Survival of the fittest tumors</h2>
<p>In recent years we’ve learned that one of the reasons tumors are hard to treat is because they <a href="http://dx.doi.org/10.1038/nature10762">evolve</a>. Some researchers believe that tumors exist only because they have evolved to hide from the immune system. This process takes years of natural selection, where only the fittest tumor cells, which effectively hide from or actively fight against the immune system, manage to survive, grow and cause major complications. </p>
<p>This means that we can expect that at least in some patients undergoing immune therapy, their tumors can evolve resistance to immune system detection and can come back. Although our immune system is capable of constantly evolving to counter viruses and bacteria, tumor evolution is a formidable enemy to overcome, and we are just beginning to understand this aspect of the disease.</p>
<h2>Challenge #4: The immune system ‘blind spot’</h2>
<p>Our immune system carries out a fine balancing act between hunting down and attacking cells that can harm us, such as viruses and bacteria, and leaving healthy “self” cells in our bodies (or good bacteria) alone. Immune cells that recognize our own normal “self” cells are killed off early during development, which prevents us from developing autoimmune disorders. </p>
<p>But most tumors result from our own cells. So how do we get the immune system to fight “self” cells it is supposed to ignore, and how do we make sure the immune system targets tumor cells, but not healthy cells? This is a big challenge for immune therapies.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Immunotherapies let T-cells do their job.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/niaid/5950870236/in/album-72157627714446209/">Healthy human T-cell via NIAID</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>By freeing T-cell brakes, current immunotherapies often work by overcoming these blind spots: immune cells suddenly start seeing our own “self” cells, which is very effective against tumors disguised as our own normal cells. The downside, however, is that this often upsets the delicate balance between autoimmunity and cancer.</p>
<p>As a result, some patients treated with immunotherapy experience <a href="http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf">autoimmune reactions</a>.
Some melanoma patients undergoing immunotherapy have been known to develop Vitiligo, a condition where that leads to the loss of skin color. Other patients undergoing treatment also report gastrointestinal distress as a common side effect from the immune system being overactivated. In extreme cases, severe life-threatening autoimmune reactions such as organ rejection can happen, indicating that immunotherapy drugs need careful examination and regulation.</p>
<h2>Overcoming the challenges</h2>
<p>Researchers are starting to sequence the DNA of tumors to get a better understanding of how they work at the <a href="http://cancergenome.nih.gov/cancergenomics/whatisgenomics/whatis">genetic level</a>. We have just begun to understand how different they are from other cells of our body. </p>
<p>Tumor DNA sequencing, along with emerging technologies, like <a href="http://www.esmo.org/Conferences/Past-Conferences/ESMO-2014-Congress/News-Articles/Liquid-biopsies-Tumour-diagnosis-and-treatment-monitoring-in-a-blood-test">liquid biopsies</a> on the blood to diagnose and monitor tumors, will help us understand how cancers evade the immune system and who will actually benefit from these treatments. In patients who do not respond to regular immunotherapies, it has been proposed that immunotherapies might be combined with conventional chemotherapies (“immunochemotherapy”) to improve potency of treatment.</p>
<p>We are also at the beginning of personalized immune therapies. This treatment involves designing vaccines made of <a href="http://dx.doi.org/10.1126/science.aaa3828">engineered immune cells</a> from a patient’s own body, to treat their own tumors. In the not too distant future, a patient may walk into a clinic, have their tumors sequenced and their immune system analyzed to decide on the best course of personalized immune therapy. </p>
<p>For now, though, we have to be careful in regulating immune therapies, and get better at understanding the intricate dance between cancers and our immune systems.</p><img src="https://counter.theconversation.com/content/40944/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sri Krishna Ph.D. does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Finding ways to use our immune system to fight cancer could pave the way for personalized cancer treatment. But to get there, we need to overcome some pretty big obstacles.Sri Krishna Ph.D., PhD Candidate, Biological Design, School of Biological and Health Systems Engineering, Arizona State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/369012015-02-18T03:32:22Z2015-02-18T03:32:22ZPeanut allergy treatment is on the horizon – but don’t drop the EpiPen yet<figure><img src="https://images.theconversation.com/files/71919/original/image-20150213-13206-vlgpy4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Avoiding peanuts is currently the only way to prevent allergic reactions.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/sharynmorrow/3052699217/in/photolist-5DKT88-53Sm9N-oNomHQ-oNoo2w-93xAGy-62u7wG-bWEvKe-dVMqvf-2nqmq8-9rPN4e-79pjrS-ayw5N5-4E6e8S-niRBmL-4U4cfX-8gHzoq-7vRdJJ-ovW44e-oNonnL-5ihiFa-6AFQ19-niRAHm-7nhGAz-6YVE6n-9nn7Ax-8sQHCK-piZE4i-9VU913-5a4478-5V4V9Z-8JXJrn-NBgcU-5Ubhzm-4wcgcQ-6UC8Tv-4nx5uY-dUtSCJ-bGhKLH-PvRcS-eb9ZMt-b9fM8r-ecj1x-6p5Sor-biKrZ4-6oMbCY-7ADVx8-7mg64d-93uuMp-dYA1YH-AyLw7">sharyn morrow/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span></figcaption></figure><p>Rates of food allergies have increased over recent decades and are at an all-time high. While we don’t know the full extent of the allergy epidemic, the <a href="http://www.ncbi.nlm.nih.gov/pubmed/19217654">rate of hospitalisation</a> for food allergies has quadrupled since the mid-90s.</p>
<p>Peanuts are one of the most common causes of food allergies. The <a href="https://www.mcri.edu.au/research/projects/healthnuts">HealthNuts study</a> tested almost 3,000 Melbourne children born between 2006 and 2009 and found 3% of infants had a confirmed peanut allergy. Only one in five children had grown out of the allergy by four years of age. </p>
<p>Researchers have made some promising steps forward in developing a treatment for peanut allergies, but there is currently no cure. Avoiding the food is the only way to prevent allergic reactions.</p>
<h2>What is a peanut allergy?</h2>
<p>Peanut allergies occur when the body’s immune system develops antibodies – called immunoglobulin (Ig) E molecules – against parts of the “harmless” peanut protein. This is known as sensitisation.</p>
<p>Sensitisation can be easily detected by measuring peanut-specific immunoglobulin E either in the child’s blood or by means of a skin prick test.</p>
<p>Allergy as a disease is seen when IgE antibodies activate the immune system. This may lead to face, lip, eye swelling, welts and hives, breathing difficulties, vomiting, and even collapse of the body’s blood circulation. </p>
<p>The most severe form of reaction, anaphylaxis, can cause swelling of the tongue and throat. This is a potentially life-threatening condition that requires emergency treatment with adrenalin autoinjectors (also known by the brand name, EpiPen).</p>
<p>But not everybody who has IgE antibodies to “peanut” will experience an allergic reaction. </p>
<p>Sometimes peanut sensitisation is found in a child who has never been exposed to peanuts. This is more common in children with eczema or children who have other food allergies. </p>
<p>In other cases, the symptoms cannot be unequivocally attributed to allergy and/or exposure to peanut. In these situations, the question has to be resolved: is it “only” peanut sensitisation or is it a peanut allergy?</p>
<h2>Causes</h2>
<p>The causes of sensitisation are unknown but <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa013536">research suggests</a> it could occur through the skin in children with eczema. </p>
<p>Other factors affecting this meteoric rise <a href="http://fooddrugallergy.ucla.edu/body.cfm?id=40">could be</a> cleaner and more hygienic environments and the delayed introduction of allergenic foods.</p>
<h2>Diagnosis</h2>
<p>If a patient presents with symptoms of allergic reaction after eating peanuts, a positive skin prick test to peanuts or detecting the presence of specific IgE to peanuts by a blood test, will confirm the peanut allergy.</p>
<p>However, if the history is ambiguous or sensitisation is seen in the absence of a known exposure to peanut, the patient may need to undergo a food challenge to confirm the peanut allergy. As this could lead to an allergic reaction, food challenges need to be performed in a clinical setting, where treatment is readily available. </p>
<p>Our <a href="http://onlinelibrary.wiley.com/doi/10.1111/cea.12258/abstract">Newcastle Peanut Anaphylaxis Predictors study</a> showed that the combination of an antibody test and a breathing test that measures a molecule called nitric oxide in exhaled air can avoid the need for a food challenge test in half of the children suspected to have peanut allergy. </p>
<p>Building on this approach, we have developed a blood test to predict anaphylaxis, which is currently being validated in a large population of children with suspected peanut allergy. </p>
<h2>Treatment</h2>
<p>Most children with peanut allergy need to carry an adrenaline autoinjector because it provides immediate relief from severe allergic reactions. </p>
<p>The uncertainty of when a severe reaction will occur places immense psychological and social burdens on patients and families. As a consequence, a number of children with peanut allergy <a href="http://onlinelibrary.wiley.com/store/10.1111/j.1398-9995.2010.02342.x/asset/j.1398-9995.2010.02342.x.pdf;jsessionid=640A3E4F5E182E01F3BDCB58DAAF21A7.f02t04?v=1&t=i636xo7b&s=b60f3b06bed2c02a7304baf21005e2ac22f32ece">suffer from</a> anxiety-based disorders. </p>
<p>Encouragingly, researchers have recently made progress in optimising immunotherapy, also called peanut “desensitisation”. In this process small amounts of peanut protein is administered regularly to build up “tolerance” to the food.</p>
<p>British scientists Leonard Noon and John Freeman were the first to show in 1911 that desensitisation to pollen could be an effective treatment for hay fever. </p>
<p>A century later, a <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060783/">study</a> with 28 children in Durham, North Carolina, showed that oral immunotherapy could reduce allergic reactions to peanut. </p>
<p>This study was subsequently confirmed by the <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2962301-6/abstract">STOP II trial</a> in Cambridge, UK where 62% of children with peanut allergy were able to eat five to ten peanuts without allergy symptoms six months after the initiation of treatment. </p>
<p>Recently, Professor Mimi Tang and co-workers from the Murdoch Childrens Research Institute, Melbourne, <a href="http://www.theatlantic.com/health/archive/2015/01/a-possible-treatment-for-peanut-allergies/385045/">studied</a> an oral probiotic peanut combination immunotherapy in 62 allergic children without previous anaphylaxis. Children enrolled in this study were regularly given small amounts of a peanut and probiotic combination so as to develop tolerance to peanut.</p>
<p>This treatment resulted in 82% of children being “tolerant” to peanuts, meaning they were able to eat roughly 20 to 40 peanuts without allergy symptoms, two to five weeks after the treatment stopped. This suggests that there may be a treatment in the future, which has a sustained effect. </p>
<p>However, treatment side-effects with oral peanut (and probiotic combination) immunotherapy are very common, with 45% to 93% of children affected. That’s why oral peanut immunotherapy can only be provided within high-level specialist care and at present is advisable to do only within research settings.</p>
<p>In future, we hope to be able to use bio-markers to predict whether children who come into contact with peanuts will have anaphylaxis and whether they’ll respond to different treatments.</p><img src="https://counter.theconversation.com/content/36901/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Rani Bhatia has received funding from Hunter Children's Research Foundation. She is an inventor on a provisional patent that describes a marker for peanut allergy </span></em></p><p class="fine-print"><em><span>Adam Collison receives funding from Hunter Children's Research Foundation and the Thrasher Research Fund. He is an inventor on a provisional patent that describes a marker for peanut allergy.</span></em></p><p class="fine-print"><em><span>Joerg Mattes receives/has received funding from the NHMRC, Hunter Medical Research Institute, Asthma Australia and the CRC for Asthma. He is an inventor on a provisional patent that describes a marker for peanut allergy.</span></em></p>Rates of food allergies have increased over recent decades and are at an all-time high. While we don’t know the full extent of the allergy epidemic, the rate of hospitalisation for food allergies has quadrupled…Rani Bhatia, Senior Staff Specialist in Paediatric Allergy and Immunology at John Hunter Children's Hospital Newcastle NSW Conjoint Lecturer in Paediatrics, University of NewcastleAdam Collison, Post Doctoral researcher - Experimental and Translational Respiratory Medicine Research Group, University of NewcastleJoerg Mattes, Professor&Chair of Paediatrics | HMRI, University of Newcastle, Australia | Senior Staff Specialist Paediatric Respiratory&Sleep Medicine | John Hunter Children's Hospital, Australia, University of NewcastleLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/318062014-09-23T05:21:20Z2014-09-23T05:21:20ZNumber of immune cells in tumours could soon help predict and treat cancers<figure><img src="https://images.theconversation.com/files/59321/original/svt9nn3p-1410968593.jpg?ixlib=rb-1.1.0&rect=0%2C6%2C507%2C315&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Head and neck cancer underway.</span> <span class="attribution"><a class="source" href="http://upload.wikimedia.org/wikipedia/commons/f/f4/PET-CT_scanning_of_lymph_node_metastases_in_cancer_2.jpg">Akira Kouchiyama</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Immune cells in the blood primarily defend us against infection. But we’re now learning that these cells can also <a href="http://www.ncbi.nlm.nih.gov/pubmed/24218361">keep us free from cancer</a>. Patients with less efficient immune systems such as organ transplant recipients or those with untreated HIV, for example, are more susceptible to cancers. It is also becoming increasingly apparent that we can use immune cells to predict survival in people who do develop cancer. And that, in fact, there are immune cells within cancers.</p>
<p>The number of immune cells inside a tumour can hugely vary: some patients have vast numbers while some have very few. <a href="http://www.ncbi.nlm.nih.gov/pubmed/24169344">In a recent study</a>, we showed that in head and neck cancers, the survival of a patient depends on how many immune cells are within the tumour. This could be a valuable way of individualising cancer treatments. Patients with lots of immune cells, for example, could be offered less toxic cancer treatment while those with few immune cells may need more aggressive treatment to improve their chances of survival. </p>
<p>Not all immune cells within the tumour are able to “attack” the cancer. By looking at specific cell markers – proteins on the cell exterior that allow us to see whether, for example, cells are exhausted – we can determine which individual immune cells in the tumour will be effective in tackling the cancer, or if they are exhausted and not able to perform any useful function. It’s possible that these exhausted cells could be reinvigorated to become useful again with targeted immunotherapy treatments currently in development. </p>
<p>These include vaccines, so if a cancer has been caused by a virus, we can vaccinate the patient with a short segment of the same virus to encourage the immune system to react to it. Around 30% of head and neck cancers, for example, are the result of human papillomavirus (HPV). There has been a 225% increase in these types of cancers <a href="http://www.ncbi.nlm.nih.gov/pubmed/21969503">over the past 15-20 years</a> and in the US, HPV will cause more of these cancers than cervical ones. In these cases, cancer cells continue to express part of the HPV on their surface. The hope is that following vaccination, immune cells will be better able to identify these HPV cancer cells and kill them. </p>
<p>For people who simply don’t have many immune cells in tumours, specific, targeted immunotherapy could be one option. But also broader “brush stroke” treatments. These broader treatments cover all immunotherapies that encourage a patient’s immune system in a fairly non-specific way. Our immune cells are normally very tightly regulated and include many fail-safe systems to prevent them from over-reacting primarily to infections. General immunotherapy takes the brakes off and allows the immune cells to react to the cancer cells.</p>
<p>It may be that a combination of specific vaccine and non-specific immune treatments could be enough in combination to tip the balance in favour of the patient’s immune system so that it is able to overcome the cancer.</p>
<p>We’re going to further investigate how immune cells might help us to fight cancer and two head and neck cancer immunotherapy trials are due to start at the University of Southampton in the next six months. One of these trials will look at a HPV cancer vaccine, while the other will investigate a non-specific immunotherapy molecule for those 70% of patients that develop head and neck cancer independent of HPV. Our hope is that within five years the results of these trials could influence the way we treat cancers.</p><img src="https://counter.theconversation.com/content/31806/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Emma King receives funding from CRUK. </span></em></p><p class="fine-print"><em><span>Christian Ottensmeier receives funding from CRUK. </span></em></p>Immune cells in the blood primarily defend us against infection. But we’re now learning that these cells can also keep us free from cancer. Patients with less efficient immune systems such as organ transplant…Emma King, CRUK Senior Lecturer Head and Neck Surgery, University of SouthamptonChristian Ottensmeier, Professor of Experimental Medicine, University of SouthamptonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/109842012-12-05T19:40:11Z2012-12-05T19:40:11ZA peek at a world with useless antibiotics and superbugs<figure><img src="https://images.theconversation.com/files/18344/original/8dj7qkcd-1354668730.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">We already know what a world without effective antibiotics would look like - just recall the pre-antibiotic era.</span> <span class="attribution"><span class="source">Lynae Zebest</span></span></figcaption></figure><p>History not only shows us our errors but also predicts our future. So, we don’t need to speculate about what a world full of superbugs and useless antibiotics would look like, we just need to recall the pre-antibiotic era (before the 1930s). </p>
<p>Our trajectory into the past is compounded by an ageing population that’s more susceptible to infections, overcrowded hospitals where infected and uninfected patients share facilities, a complacency toward basic hygiene principles and globalisation and its attendant increase in medical tourism that provides a free flight for any superbug seeking a new home.</p>
<p>In the absence of effective antibiotics, management of infected patients will be reduced to cleaning wounds and applying topical antiseptics. And removing the focus of infection, which could be a whole limb. The problem is that many of the infections we see in hospitals are actually acquired in the hospital itself and affect patients who are at their most vulnerable, having had heart surgery or other urgent procedures. </p>
<p>Exacerbating this is our reliance on intravenous tubes and catheters that measure blood pressure or deliver drugs to patients, particularly in intensive care units. These provide a veritable freeway, allowing superbugs to gain direct entry into our bodies. </p>
<p>The rise of superbugs could herald an era of deferring all non-essential surgery and caring for the sick outside of hospitals or with minimal intervention wherever possible. Perhaps quarantine hospitals and sanatoriums will be needed to separately house infected patients in the hope that good nutrition and rest will enable their immune systems to tackle the infection.</p>
<p>Technical and medical advances may provide new hope but let’s not forget the lessons of the past, which clearly demonstrated that simple hygiene has a huge impact on controlling infections. All hospitals should be able to provide patients with individual bathrooms and place a greater emphasis on physically separating patients who have resistant infections from people who are uninfected but highly susceptible. </p>
<p>We will need to prioritise cleaning of hospital areas to ensure that superbugs don’t persist in the environment. And novel immune therapies may hold some promise for the infected patient in the era of failing antibiotics. </p>
<p>Immune therapies try to boost the body’s natural defences against microbes because our immune system has evolved to eradicate infecting microorganisms. Some immune cells are dedicated to engulfing and killing invading microbes while others find and kill any resident cells that are infected with microbes.</p>
<p>Each cell in our body is equipped with a suicide program that’s activated if the cell senses that it’s infected. Some microorganisms have developed mechanisms to counter immunological onslaughts, either by switching off the suicide program or by exhausting or paralysing immune cells. <a href="http://www.ncbi.nlm.nih.gov/pubmed/21295337?dopt=Abstract">Research into the immune system</a> has provided insights into how we can enhance immunity to eradicate infections, regardless of whether the infecting organism is resistant to antibiotics. </p>
<p>The advantage of boosting immunity is, of course, that it offers a common platform to tackle many bugs. Traditionally, antibiotics only kill one type of microorganism or group of microorganisms. The advantage of immune therapies is that they can be used against many – maybe all – infections. This would also make it very difficult for microorganisms to become resistant because that would take many years of evolution. </p>
<p>Immune therapies can take the form of <a href="http://www.ncbi.nlm.nih.gov/pubmed/19396174?dopt=Abstract">administering additional immune “hormones”</a>, which are natural proteins in our bodies that facilitate immunity. By giving additional quantities of these “hormones”, we can promote the function of immune cells. Animal studies have indicated that these types of therapies hold much promise and human studies are underway. Another type of immune therapy is administering drugs that switch on the suicide program in infected cells where the program has been disabled by the infecting microbe. </p>
<p>Most importantly, we mustn’t forget the great success of vaccines, which promote immunity to prevent infection. Basically, they arm the immune system by providing it with a clear picture of the enemy, so that immune cells are at the ready. Indeed, vaccination is the most successful medical intervention of all time because it has facilitated the eradication of several viruses. We must now try to <a href="http://www.ncbi.nlm.nih.gov/pubmed/22617834">apply this success to bacteria</a>. </p>
<p>At the height of the antibiotic era, we felt secure that the microbe was conquered. Our lack of insight and complacency has made us look foolish and arrogant as microbes are retaking their position as the major cause of human suffering and death. </p>
<p>The lessons we’ve already learnt, along with pioneering research, will hopefully provide us with an advantage in combating infections so that, in the future (tempered by greater wisdom), we can feel more secure that microbes and the diseases they cause can be conquered with novel therapies and good management.</p>
<hr>
<p><strong>This is the seventh article in Superbugs vs Antibiotics, a series examining the rise of antibiotic-resistant superbugs. Click on the links below to read the other instalments.</strong></p>
<p><strong>Part one:</strong> <a href="https://theconversation.com/washing-our-hands-of-responsibility-for-hospital-infections-10652">Washing our hands of responsibility for hospital infections</a></p>
<p><strong>Part two:</strong> <a href="https://theconversation.com/superbugs-human-ecology-and-the-threat-from-within-10765">Superbugs, human ecology and the threat from within</a></p>
<p><strong>Part three:</strong> <a href="https://theconversation.com/we-can-beat-superbugs-with-better-stewardship-of-antibiotics-9492">We can beat superbugs with better stewardship of antibiotics</a></p>
<p><strong>Part four:</strong> <a href="https://theconversation.com/the-hunt-is-on-for-superbugs-in-australian-animals-10699">The hunt is on for superbugs in Australian animals</a></p>
<p><strong>Part five:</strong> <a href="https://theconversation.com/the-last-stand-the-strongest-of-the-superbugs-and-their-antibiotic-nemesis-10727">The last stand: the strongest of the superbugs and their antibiotic nemesis</a></p>
<p><strong>Part six:</strong> <a href="https://theconversation.com/unblocking-the-pipeline-for-new-antibiotics-against-superbugs-10990">Unblocking the pipeline for new antibiotics against superbugs</a></p>
<p><strong>Part eight:</strong> <a href="https://theconversation.com/trading-chemistry-for-ecology-with-poo-transplants-10755">Trading chemistry for ecology with poo transplants</a></p>
<p><strong>Part nine:</strong> <a href="https://theconversation.com/new-antibiotics-whats-in-the-pipeline-10724">New antibiotics: what’s in the pipeline?</a></p><img src="https://counter.theconversation.com/content/10984/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Marc Pellegrini receives funding from NHMRC and the CASS Foundation.</span></em></p>History not only shows us our errors but also predicts our future. So, we don’t need to speculate about what a world full of superbugs and useless antibiotics would look like, we just need to recall the…Marc Pellegrini, Researcher, Walter and Eliza Hall InstituteLicensed as Creative Commons – attribution, no derivatives.