Breakthroughs in children’s medicine
CANCER
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Professor Darren Hargrave.
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Welcome to this cancer breakthrough guide – a journey through one of the most dynamic fields of childhood medicine. I’ve worked as a researcher and doctor in the field for more than 20 years. In that time, rapid scientific progress has transformed survival rates and, today, children who would’ve lost their lives a decade ago are alive and well. But we have a long way to go. Cancer remains the leading cause of death in children aged one to 14. Four or more children die from cancer each week in the UK*. At Great Ormond Street Hospital (GOSH), we see children with the rarest and most complex types. Some have exhausted their treatment options and are facing the most heartbreaking of outcomes. In fact, before the coronavirus outbreak 2,062 of our cancer patients were on clinical trials – demonstrating just how desperately they need new treatments.
era of targeted, personalised medicine. We often talk about GOSH being world leading. But we don’t work in isolation. With some of the rarest cancers affecting only a few children a year, it’s vital to work with others to gather data and understanding from as many patients as possible. Thanks to supporters like you, we now have incredible systems in place across the globe that are making it easier for us to connect and share knowledge. Thanks to kind supporters like you, we’re seeing even more children surviving and thriving. I know GOSH, and you, will play a central role in what comes next. Thank you. Professor Darren Hargrave
GOSH researchers are working on exciting scientific ideas. Genetic understanding is shifting towards an
GOSH Charity Clinical Professor of Paediatric Neuro-oncology.
*www.cancerresearchuk.org/health-professional/cancer-statistics/childrens-cancers#heading-One 3
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CONTENTS
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Page
Childhood cancer: types and treatments ............................................................................................................................................................................................................. 06
Yesterday Cancer: an insurmountable challenge? .................................................................................................................................................................................................................... A vision to change the future of children with cancer ........................................................................................................................................................ Scaling the mountain .................................................................................................................................................................................................................................................................................................... Collaboration: the key to success ................................................................................................................................................................................................................................................. Mini transplants with major outcomes ........................................................................................................................................................................................................................
Today A picture of health .................................................................................................................................................................................................................................................................................................................. Targeted treatments: the rise of CAR T-cells .................................................................................................................................................................................................. Meet the team ................................................................................................................................................................................................................................................................................................................................... Meet Austin ................................................................................................................................................................................................................................................................................................................................................ Dual-use drugs ................................................................................................................................................................................................................................................................................................................................ Bringing it all together: supporting the entire cancer journey .................................................................................................................
Tomorrow A bold ambition: 100% survival and kinder treatments ................................................................................................................................................ The next generation of CAR T-cell therapy ........................................................................................................................................................................................................ The genetics revolution ........................................................................................................................................................................................................................................................................................... Translating CAR T-cells for tumours .......................................................................................................................................................................................................................................
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Cover image: Your support will help nine-year-old Gabriel fight acute lymphoblastic leukeamia, a rare and aggressive cancer, and fund the Play team who he loves playing with when he’s at GOSH. 5
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Childhood cancer: types and treatments Cancer happens when something goes wrong with the genetic code (DNA) inside cells, causing them to multiply out of control. It can happen to any type of cell in the body, from skin cells to heart cells. Cells that divide frequently are the most likely to become cancerous, because the more they divide, the more chances there are of errors creeping into DNA.
Children at GOSH have some of the most complex, rare and difficult-to-treat types of cancer. These include blood cancers like leukaemia, and tumours growing in delicate areas of the body such as the brain and spinal cord. The most life-threatening are those that come back after treatment, or that do not respond to treatment at all. Treatment usually consists of a multipronged attack, sometimes involving radiation therapy (radiotherapy), drugs infused into the body (chemotherapy), surgery to remove cancerous tissue, and more. As scientific understanding progresses, treatments are changing, becoming more tailored to the specific cancer type and even the individual child it affects.
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Ch e
s
m
y and cell the rap rap he t ie o
Brain tumours. Eg. diffuse intrinsic pontine glioma (DIPG)
therapy dio Ra
Blood cancers. Eg. leukaemia
Sur ge ry
Tumours elsewhere in the body. Eg. Neuroblastoma, Wilms tumour
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YESTERDAY
Nurses on the hospital wards in the 1950s.
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Cancer: an insurmountable challenge? On 18 April 1895, a young boy from Islington was admitted to the Hospital for Sick Children – which we now know as GOSH. Percy was only 17 months old and his hospital notes show a diagnosis of leucocythaemia – an early description for leukaemia. Doctors could do nothing for little Percy and, within 12 days, he had died. He was just one of thousands of children who came to the hospital during these early years with life-threatening diseases. For decades to come, death was sadly the tragic outcome for most children with cancer. There was no specialist cancer ward at the hospital and treatment options were limited. Some localised solid tumours, such as those of the kidney (Wilms’ tumour), might be cured by surgery alone, but the majority could not be controlled.
Leukaemia was simply thought to be incurable – a medical text from 1914 suggested arsenic as having ‘undoubted but temporary value’. Drugs designed to destroy dividing cells – chemotherapy – were still new and were only really able to prolong life, not save it. Cancer almost always returned and invariably proved fatal. It was only from the 1950s, with the help of pioneers at GOSH, that startling breakthroughs began to move things forward.
Right: The original hospital premises at 48–49 Great Ormond Street, 1870s.
1845 Leukaemia first identified as rare and fatal disease of the blood. 1852 The Hospital for Sick Children (now Great Ormond Street Hospital) opens. 10
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A vision to change the future of children with cancer Still only in his 30s, Dr Roger Hardisty – later to become Professor Hardisty – joined GOSH in 1958. Despite not having any formal training as a paediatrician, without patients directly under his care and without a specialist cancer ward, he made remarkable steps in understanding and treating leukaemia, as well as identifying various forms of the disease for the first time. In his three decades at the hospital he was pivotal in reducing the devastating 100 per cent death rate for children with leukaemia to 70 per cent. As always, brave patients and their families played a major role in this dramatic progress. In 1960, six-yearold Susan Eastwood died within two months of being diagnosed with leukaemia. This terrible loss inspired
her family to launch what would become a highly influential fundraising appeal. It made the headlines by raising £3,000 in little over a year (about £50,000 in today’s money), and it was the first donation to the hospital from the Leukaemia Research Fund. When posed with the question “Are we prepared to have a go at tackling leukaemia?” Dr Hardisty gave an emphatic “Yes!”, despite Gordon Piller, the fund’s founder, likening the problem to climbing Everest with little equipment or knowledge of how to get to the top. Out of this came the country’s first leukaemia research unit, based at GOSH and its partner the UCL Institute of Child Health. Led by Dr Hardisty, this unit began looking for the origins of the disease, testing new treatments against a background of near total fatality.
1958 Dr Hardisty joins the hospital, where he will become a driving force behind remarkable changes in children’s cancer care. 12
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Dr Roger Hardisty.
1961 The UK’s first leukaemia research unit opens at Great Ormond Street Hospital.
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Scaling the mountain In the early years of his research, Dr Hardisty sought out long-term leukaemia survivors – those children whose disease had not returned for more than four years. He could only find 100 patients – about one per cent of all cases – proving just how accurate the Everest comparison had been. He grew leukaemia cells in the lab, testing treatment after treatment in search of the most effective. In cases where drugs had successfully killed the cancerous cells and the child had entered remission, there was still little hope of a full recovery. Once the drugs were stopped, the cancer would come back, with symptoms such as bone marrow failure, anaemia and bleeding. And, even when there was success in killing the leukaemic
cells, many children died of common infections because of the damage the drugs had done to their bodies. The situation with other cancers in the 1960s was not much better. Children with neuroblastoma, a particularly aggressive cancer that causes tumours to grow in nerve tissue, had less than a seven per cent chance of surviving more than two years from the time of diagnosis. Surgery was only an option for certain tumours and was rarely curative. In addition to this stark prognosis for patients, there was little culture for local doctors to refer cancer patients to specialists. That meant many children simply missed out on the chance of receiving potentially life-saving new treatments.
1962 Fewer than one in 100 children with leukaemia survive longer than four years. 1970 Long-term leukaemia survival rates increase by three times that of the 1960s. 14
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By the 1970s, some of the hospital’s early research efforts were starting to show real reward. Chemotherapy was improving. Surgical techniques were becoming safer. Microscopic and genetic research techniques were becoming more sophisticated, allowing researchers to better identify the many different types of cancer, as well as beginning to understand how each would respond to different treatments. A 1971 study showed that long-term survival for children with acute leukaemia had trebled since 1963.
Right: Article from The Times, 7 December 1961. 15
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Collaboration: the key to success An enduring problem was that no single hospital saw more than a handful of children with any one type of cancer. The resulting variability in how different local and specialist hospitals treated their patients meant it was almost impossible to gather meaningful evidence and test new therapies rigorously. Dr Hardisty led the first national cancer studies, funded by the Medical Research Council. These trialled a new treatment for acute lymphoblastic leukaemia (ALL), a common form of childhood cancer. By delivering radiotherapy early to the brain and spine, the trial showed it was possible to kill ‘hidden’ leukaemia cells in the cerebrospinal fluid, stopping the cancer from coming back in a significant number of patients.
as lead clinical consultant. Along with Dr Jon Pritchard, Dr Chessells helped to set up the UK Children’s Cancer Study Group in 1977. Medical teams around the UK could now pool ideas and standardise the way patients were given experimental treatments. Dr Pritchard transformed the way chemotherapy was used to treat childhood cancers like liver tumours and neuroblastoma, introducing the now widely used drug Cisplatin into treatment regimes. At the beginning of his career, the overall prospect of survival in childhood cancers was 30%. Now it is more than 75%.
Right: The hospital’s first cancer consultants, Dr Judith Chessells (middle) and Dr Jon
In 1973, GOSH opened a specialist fivebed cancer unit, with Dr Judith Chessells
Pritchard (right), with fellow haematologist and oncologist, Dr Ian Hann.
1973 Dedicated cancer inpatient unit established at Great Ormond Street Hospital. 1977 Hospital consultants set up the first UK-wide Children’s Cancer Study Group to promote research 16
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Dr Chessells recalls: “I remember the very first Study Group day for paediatricians where Roger presented his vision that things had to be better. Many were reluctant to refer patients to specialist centres to investigate and treat what they thought were fatal diseases. But, with enough effort, and the success we showed with children treated on the early collaborative cancer trials, support for these new ways of working grew. The UK Children’s Cancer Study Group meant we could be sure even children with rare types of cancer received the latest and best treatments.”
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Mini transplants with major outcomes The huge strides taken in the 1960s and ‘70s to improve cancer research and treatment meant more children than ever were surviving. A further series of breakthroughs in treating leukaemia would come from the launch of the hospital’s bone marrow transplant programme in 1979. GOSH Immunologist Professor Roland Levinsky developed a technique to isolate immune cells in the blood. This made it possible to extract working immune cells from a healthy donor and transplant them into a child – known as a bone marrow transplant. The idea was to replace cancerous blood cells with healthy ones. In the programme’s early days, not many children could undergo the treatment. It involved intensive chemotherapy
to kill off existing bone marrow cells, creating space for the transplant. This wiped out the patient’s own immune system, leaving children already weakened by leukaemia unable to fight infection and at severe risk of organ failure. Those who did receive a transplant and survive often faced side effects including hair loss, sore mouths and guts, and irreversible infertility. Since then, GOSH researchers have applied their growing knowledge of how children’s immune systems work to find better way of ensuring a successful transplant. They used antibodies – which can target only certain immune cells in the body – to create space for the bone marrow transplant without using high doses of chemotherapy. This meant more children could be offered the treatment, with far fewer side effects.
1999 Dr Paul Veys develops a kinder bone marrow transplant that is gentler, with less intense chemotherapy and can help children who are too sick for standard doses of drugs. 18
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Graph showing long-term survival of children treated with a bone marrow transplant at Great Ormond Street Hospital since 1978. 60 survived deceased
Number of patients
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Year of transplant Above: Data supplied by Ashley Waterman, Bone Marrow Transplant unit, Great Ormond Street Hospital.
1979 The hospital launches its bone marrow transplant programme.
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TODAY 20_12_IG_Legacy_Cancer Breakthrough Guide_booklet_UPDATE_ST2.indd 20
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A picture of health The impact on imaging in medicine (radiology) has also been transformative. For childhood tumours, techniques like MRI and CT – introduced in the 1970s and 80s – are now vital for both diagnosing the cancer and identifying its exact parameters. This is particularly important for planning surgical removal of brain tumours, where a mere millimetre error could mean damaging healthy brain tissue. Professor Chris Clark and his neuroimaging team at GOSH are now using advanced MRI techniques, including diffusion tensor imaging (DTI) and tractography, to visualise vital nerve pathways and map out connections between different parts of the brain. This helps surgeons to plan even more precise procedures.
GOSH hopes to open an incredible new intra-operative MRI suite, which allows imaging of a child’s brain during an operation. Brain structures can shift slightly during surgery, so the technique should further improve the chances of removing all cancerous tissue. Radiologists can now see the shape, position and shadows of organs and tumours, as well as chemical reactions inside individual cells, too. Known as nuclear medicine, the approach uses a special camera to track drugs as they pass through the body and show whether cells are responding to treatment for conditions like leukemia. If they’re not, doctors can rapidly begin a different regime. GOSH has ambitious plans to install the most sophisticated of these scanners, known as a PET-MR, as part of the next phase of its rebuilding programme.
2015 A 3T MRI scanner was installed in Turtle ward, giving surgeons the optimum information for their decision-making. The future The Khoo Teck Puat iMRI Suite, an incredible new intra-operative MRI suite will allow imaging of a child’s brain during an operation, which should further improve the chances of removing all cancerous tissue. 22
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Image of a 3T MRI Prisma scanner at GOSH.
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Targeted treatments: the rise of CAR T-cells While broad-brush treatments like chemotherapy and radiation can destroy cancer cells effectively, damage to healthy cells is unavoidable. Our immune systems are programmed to fight off viruses and bacteria, but aren’t great at fighting off cancer, because it’s caused by our own cells multiplying out of control. Our immune system has difficulty recognising it as a threat and doesn’t attack it. In the last decade, researchers have discovered a way to remove the cancer ‘blindfold’ on our immune systems and a new wave of targeted cancer treatment has arrived. These therapies are ‘locked on’ to cancer cells, concentrating their full power where
it’s needed most. Damage to healthy tissue is minimised or nonexistent, vastly reducing the risk of side effects. One promising technique involves modifying the genetic code inside the body’s own immune cells, enabling them to recognise, hunt down and destroy cancer cells. These modified cells are known as CAR T-cells. GOSH researchers are leading the way in Europe in applying this incredible technology to acute lymphoblastic leukaemia (ALL) that has come back after treatment. In 2015, the first child in the world was treated with ‘universal’ CAR T-cells at GOSH and, in 2018, GOSH became the first hospital in the UK to
2013 Launch of one of the first European CAR T-cell studies, pioneered by Professor Persis Amrolia. It paves the way in this rapidly emerging field, but this type of CAR T-cells have now been superceded by ‘next generation’ cells that are more effective. 2015 GOSH immunologist Professor Waseem Qasim used CAR T-cells to treat a oneyear-old patient with ‘incurable’ leukaemia. His incredible world-first sparked a new wave of CAR T-cell research around the world. 24
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treat patients with the licensed CAR-T therapy as part of standard care. A new CAR T-cell therapy for relapsed ALL, developed by GOSH specialists Professor Persis Amrolia and Dr Sara Ghorashian, is being offered to children through a clinical trial known as CARPALL. Early results suggest this treatment could cause less side effects than existing CAR T-cell therapies, as well as potentially clearing the disease more effectively. Now, researchers are working hard to improve CAR T-cell therapy, ensure it is available for all children who could benefit, and to apply it to other types of cancer.
A new wave of targeted cancer treatment has arrived – CAR-T cell therapy.
2018 An 11-year-old boy at GOSH becomes the first NHS patient to receive CAR T-cell therapy. A landmark agreement between NHS England and the drug manufacturer means the drug (Kymriah) can now be offered to eligible NHS patients with relapsed ALL. 2019 Results of the CARPALL clinical trial at GOSH suggests a new CAR T-cell therapy has less side effects and could be more effective at treating ‘incurable’ ALL than similar treatments.
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Meet the team Diagnosis with a brain tumour can bring family life to a standstill in the worst possible way. But it also sparks an immediate flurry of activity, as a multi-disciplinary GOSH team springs into action around the child and their family. From radiology and genetics to nursing and psychology, these experts provide support and care at every stage of the patient’s journey.
Karen Howe Advanced Nurse Practitioner “I became GOSH’s first cancer research nurse in 2000. The role involves offering support and guidance through what can often be a very challenging and uncertain period. “I’m now the first Advanced Research Nurse Practitioner for childhood cancer trials at GOSH, providing expert advice, leadership and education to the wider research and clinical team, as well as undertaking clinical reviews of patients enrolled on trials. The most rewarding part of my role is building relationships with the children and their families, while assessing how they are getting on with the new treatment.”
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Professor Thomas Jacques Neuropathologist
Professor Chris Clark Brain Imaging Expert
“I study tumour samples collected from patients across the UK to better understand how cancers develop, progress and resist treatment.
“Every child with a tumour has an MRI scan to help us understand exactly where it is and whether it could be removed surgically. It’s key for diagnosis and monitoring, particularly tracking how their tumour changes or responds to treatment. Some brain tumours can affect vision, as they grow into the optic pathway.
“We’re now able to study genetic information in much more detail, including how a single DNA mutation during a child’s development can lead to cancer. Insight like this could help us better treat these children. We’re also finding that new kinds of genetic analysis can help to more accurately diagnose sub-types of cancer, which will help doctors to choose the treatment most likely to work for each child.”
“My team is developing advanced MRI techniques that show up microscopic damage to optic nerve tissue, before it’s had any effect on the child’s vision. The idea is we could intervene at this point and perhaps prevent any sight loss from happening at all.” 27
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Meet Austin Austin, 11, from Whitley Bay, north-east England, was diagnosed with acute lymphoblastic leukaemia (ALL) at the age of two. By the age of eight, he had dealt with three relapses and exhausted all traditional treatment options including radiotherapy, chemotherapy and two bone marrow transplants. His dad Scott says, “When Austin relapsed for a fourth time, our world came crashing down. We thought we had exhausted every option. We found out there was a trial available for Austin at GOSH and had a lifechanging meeting with Professor Persis Amrolia. I remember that day so clearly. He was talking about potential hope, and suddenly we could see a future both for Austin and for medicine. The CARPALL trial would offer a completely different form of treatment.
“Austin was so fortunate to have this option available to him. He had the cells at GOSH in October 2016 and we found out on his birthday at the end of that month that the cells were doing exactly what we needed them to do. “Two and a half years later, Austin is doing so well. He is more physical then he has ever been. He is a big fan of his scooter. Every night he is at the scooter park with his friends. It is lovely to see him full of energy. When he was in isolation and spent weeks and months in one room he loved Lego, it was all we could do to keep him entertained in such a small space. What is amazing to see now, is the Lego still has the lid on it, and his scooter is nearly worn out.”
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Austin and his family.
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Dual-use drugs Developing new drugs from scratch takes a huge amount of time, tenacity and money. So, in recent years, Dr Owen Williams and his team have taken a different approach. By examining a comprehensive catalogue of existing drugs, developed for anything from the common cold to HIV, they’re hunting for off-the-shelf treatments that could offer benefits for children with life-threatening cancers. Because the team is working with existing drugs already proven to be safe, they could be accelerated through to the clinic faster, cheaper and more easily than new drugs. This is known as drug repurposing. Central to its success is identifying key mechanisms causing the cancer and looking for existing drugs that could counteract them. Remarkably, several drugs – including mebendazole, usually prescribed to
treat parasitic worms – have already shown great promise in helping children with acute myeloid leukaemia (AML). These drugs effectively block key cancer-boosting processes inside cells. AML is diagnosed in around 90 children in the UK every year and, despite dramatic improvements in treatment, around a third will lose their lives within five years of diagnosis. While other researchers are pushing forward promising new treatments like CAR T-cell therapy, Dr Williams’ team hope existing drugs like mebendazole could offer ‘quick win’ approaches to help these children sooner. They’re also trawling the library for dual-use drugs to help children with other difficult-to-treat cancers, including the fatal brain tumour diffuse intrinsic pontine glioma (DIPG).
2020 Dr Owen Williams plans to initiate the UK’s first trial of an anti-worming drug to treat acute myeloid leukaemia (AML). 30
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Dr Owen Williams.
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Bringing it all together: supporting the entire cancer journey At GOSH, children with cancer have access to extensive ‘wrap-around’ care. These services, all funded by GOSH Charity, are designed to make life easier for families as they go through their cancer journey at GOSH, particularly as there’s increasing evidence a holistic approach to care can help children recover more quickly and reduce the risk of associated mental health problems. Recovery can also be affected by the environment a child is treated in. A 2018 study of children undergoing surgical procedures at GOSH showed that inpatient stays were 2.4 days shorter in newer facilities – designed to be comfortable, spacious and to put children at ease. In the future GOSH will plan to transform its clinical facilities further, with new cancer wards designed around children. Research will be embedded in every child’s cancer journey, from giving them access to the latest treatments
through clinical trials, to collecting data remotely after they’re discharged. This plan hopes to include incredible new imaging facilities, intensive care units and a state-of-the-art pharmacy. Not just small adults GOSH is uniquely positioned to treat the multitude of health issues children with cancer may be facing. Intensive chemotherapy can make eating impossible because the throat lining is damaged. Brain tumours can press on the optic nerve, causing vision changes. Cancer treatments can also cause a number of long term side effects. No matter the issue, GOSH has experts who can help, from dieticians and childhood pain experts to palliative care teams, all supporting families. Children can’t simply be considered a ‘small adult’ when it comes to medicine. The vast range of paediatric expertise at GOSH means, in many cases, children with cancer have every expert they need, under one roof.
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Eden at two years old.
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TOMORROW
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Tomorrow
A bold ambition: 100% survival and kinder treatments In the 1800s, there were few treatments for childhood cancer. Despite dramatic improvements, in hard-to-treat cancers just five out of 10 children survive. Researchers at GOSH are developing the treatments of tomorrow. Franks story Frank was born in January 2017. He was a healthy baby, weighing 9lbs. He was hardly ever ill, but things changed the day before his second birthday. Frankie was diagnosed with leukaemia. “It was a shock. I felt like I had my legs taken out from under me. The news turned our world upside down,” mum Maris says. Frankie was taken straight to GOSH where he started chemotherapy. After four weeks, Frank wasn’t responding to treatment. “We hoped that Frankie didn’t have the nasty type of the disease, but we had to prepare ourselves,” Maris says . “Even when the leukaemia spread to Frank’s brain, we still had hope.”
“Frank was energetic and was known by everyone as always being very smiley. We called him our little monkey. The clock stopped for us when we were there with him at GOSH. We talked to him, played with him, played his favourite cartoons and favourite music. Every moment was precious. We tried so hard to stay strong for him until the very end. “I want to do something for Frank and to build a legacy for him. I have a genuine interest in the etiology (the cause) of Frank’s condition. I know it was caused by a random gene mutation, but I still don’t understand why. It’s so difficult to get funding for rare cancers because there are so few cases. The last patient to have Frank’s specific type of T-ALL at GOSH was five years ago – that’s how rare it is. I hope my voice and Frank’s story can help get funding for research that will help us better understand T-ALL and how to treat it.” Right: Frank (pictured with his parents), was treated for a rare type of T-ALL at GOSH.
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The future The UK’s second NHS proton-beam therapy facility at University College London Hospital (UCLH), with children treated in partnership with GOSH. Due to open in 2021.
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Tomorrow
The next generation of CAR T-cell therapy Training immune cells to recognise, hunt down and destroy cancer cells – known as CAR T-cell therapy – has shown promise in treating childhood leukaemia (see page 24). But some key challenges remain. Cancer cells can evolve in response to the treatment, putting up defences that make CAR T-cells less effective. Dr Sara Ghorashian says: “They produce blocking substances or change the way they appear in an attempt to escape recognition by the CAR T-cells. “We’re developing a new generation of CAR T-cells, engineered in the laboratory to carry extra ‘equipment’ that will help them keep going, even when the tumour is trying to stop them doing their job.” One of these new weapons is an ability to recognise more than one unique marker on the surface of cancer cells.
That means if the cancer cells evolve to shed one marker, the CAR T-cells should still be able to lock onto their target. Another challenge is cases where patients are too ill to spare their own T-cells. Sadly, these patients currently have little hope of recovery. But Professor Waseem Qasim hopes to change that: “We’re creating ‘universal’ CAR-T cells, known as UCART. These are sourced from volunteer donors but modified so they can be used without being specifically matched to the child. We successfully treated the first child in the world with these cells in 2015.” Another key area of research is improving manufacturing techniques, to ensure CAR T-cells can be made in large volumes. GOSH researchers are working hard to create CAR T-cells targeted at other life-threatening cancers.
2020 T he next phase of the CARPALL study will open, using more advanced CAR T-cells engineered to recognise an additional target on the surface of leukaemia cells. 38
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How CAR-T therapy works Immune cells Cancer cells
1. Immune cells don’t recognise that cancer cells are harmful.
2. In CAR-T therapy, immune cells are taken from the patient and engineered to recognise cancer cells.
3. When given back to the patient, these engineered cells can then recognise and destroy cancer cells.
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The genetics revolution All cancers are caused by changes inside cells that alter their DNA instructions, leading to uncontrolled cell division. Understanding how and when those genetic changes occur could lead to more rapid diagnostic techniques, predicting cancer risk or even, in future, stopping it from happening altogether. “A decade ago, our primary diagnostic tool for cancer was looking at the cells under a microscope,” says Dr Darren Hargrave. “Genetics is revolutionising the way we diagnose and treat these and other diseases.” “Studies have shown that for virtually every ‘type’ of cancer, there are many sub types, each with different genetic characteristics. That’s telling us incredibly valuable things about
which existing treatments are likely to work for which types, as well as giving us new ideas for treatments.” In 2018, Professor Hargrave launched a UK-wide project (SMPaeds) to sequence the DNA of all childhood tumours that have returned after treatment. These cancers are often resistant to further treatment and therefore have an extremely poor prognosis. “We’re hoping to see the underlying instructions driving the cancer’s behaviour, including exactly how it puts up barriers against treatment. We’ll also look for genetic instructions that create unique features on the surface of cancer cells. That’s exciting because the more of those we have, the more we can target our treatments.”
2019 P rofessor Kathy Pritchard-Jones shows that genetic precursors to Wilms tumour can be found in healthy looking kidney tissue surrounding the tumour. Identifying where cancer may be ‘lying in wait’ could lead to more targeted surgery. 40
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Tomorrow
From 2019, the NHS is offering all children with cancer whole genome sequencing – analysis of their entire DNA sequence. In 2018, GOSH became one of seven Genomic Laboratory Hubs (GLHs) commissioned by the NHS to deliver this sequencing. The initiative builds on the 100,000 genomes project, a national initiative in which GOSH played a lead role. GOSH is uniquely placed to drive this pioneering work forward. As of 2019, it is the most digitally advanced hospital in the UK, with a centralised electronic patient record system and linked analytics platform to enable pioneering research. The new Zayed Centre for Research into Rare Disease in Children houses state-ofthe-art facilities to support genetic
research, including world-class gene and cell therapy laboratories. Experts across GOSH are working closely with leaders in the field, from launching international clinical trials and partnering with organisations like Cancer Research UK, to collaborating with the Wellcome Sanger Institute, a world-leader in genetics that played an integral part in sequencing the first human genome.
2019 A s part of a national childhood cancer collaboration INSTINCT, Professor Thomas Jacques shows that molecules blocking DNA instructions from being read can provide key information about which treatments are likely to work. 41
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Tomorrow
Translating CAR T-cells for tumours Despite promising technologies like proton beam, they won’t work for all. Brain tumours are one of the most common causes of cancer death in children. One particularly devastating brain tumour is diffuse intrinsic pontine glioma (DIPG) – a brainstem cancer diagnosed in around 30 children each year in the UK. Because it grows diffusely within vital brain tissue it’s usually impossible to treat, even with techniques like proton beam. Despite significant research into better treatments, the average survival for a child after diagnosis with DIPG is just nine to 15 months. Dr Karin Straathof is developing a pioneering yet familiar new treatment for children with lifethreatening tumours: CAR T-cell therapy.
“We believe it could be just as powerful for treating childhood tumours, like DIPG and neuroblastoma,” says Dr Straathof. “We just need to adapt the approach. It’s trickier when the cancer isn’t in the blood or bone marrow, where T-cells can more easily find tumour cells. “We’re developing CAR T-cell therapy, to save more of these young lives. But also, because it’s so targeted, we hope it can ensure children live happier and healthier lives afterwards, free of side effects of treatment. “Some of our challenges are the same, such as cancer cells losing their unique marker. Others are unique to solid cancers, such as ensuring CAR T-cells can reach tumours and stick around long enough to shrink them.”
2016 GOSH researchers launch the UK’s first clinical trial of CAR T-cell therapy for childhood neuroblastoma. Early results are promising but suggest higher doses may be required compared with CAR T-cell treatments for blood cancer. 42
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Dr Karin Straathof.
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THANK YOU We’ve come a long way since the Hospital for Sick Children opened in 1852. The hospital’s dedicated and passionate staff have pioneered many new and better ways of treating children with some of the most life-threatening conditions. But we are yet to find a cure and kinder and more effective treatments for all childhood cancers. Throughout the hospital’s history, it has been the continued and generous support of our donors that has helped to fund the research that provides new breakthroughs. With your ongoing generosity, we seek to give hope to all children that needs specialist help.
Great Ormond Street Hospital Children’s Charity. Registered charity number 1160024.
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