Republished from article written by Dr Ingo Ringshausen for The Conversation.

Cancer of the immune system, called lymphoma or leukaemia, generally affects the entire body’s bone marrow and lymph nodes. Because these types of cancers are so widespread, surgery isn’t useful, so patients are usually treated with chemotherapy. Although these treatments have become significantly better in the past ten years, lymphoma and chronic leukaemia often come back months or years after treatment.

Effective treatment options for these types of cancer become increasingly limited over time as tumours become resistant to chemotherapy after several rounds of treatment. For most patients, a cure is out of reach, so the goal of treatment is instead to control the cancer for as long as possible. There’s a huge need to improve therapies that can eliminate cells that are resistant to chemotherapy and prevent the disease from reoccurring.

However, Ingo and his colleagues recently identified a new achilles heel of blood cancers. Their research found that treating the normal cells near to the cancer cells with a type of drug known as small molecule inhibitors significantly improved the effects of a broad range of chemotherapies.

In fact, in one test, this combination therapy extended the length of survival over 90% longer than using chemotherapy alone. This shows that cancer cells which would normally have resisted and survived chemotherapy, could now be eliminated from the body. Not only does this give patients a new kind of treatment, it also has the potential to cure patients who have to live with the disease for the rest of their lives.

You can also watch a short video about this here.

Recent months have seen increasing excitement over the new wave of cellular immunotherapies. These complex novel treatments use immune cells that are taken from a patient, genetically modified with a Chimeric Antigen Receptor (CAR) to target a specific cancer, expanded into large numbers and then re-infused. In 2018 Cambridge University Hospitals NHS Foundation Trust ran a successful first-in-NHS trial of a similar therapy for metastatic melanoma, and subsequently has been selected as one of only three UK centres for Zuma-8, a major international study of CAR T-cells in chronic lymphocytic leukaemia. Following inspections of the site by Kite, one of the two largest CAR T-cell manufacturers, the study is scheduled to open in Cambridge in October.
 
The success of the Cellular Immunotherapy programme in Cambridge led in April to the selection of Cambridge University Hospitals as one of three new national centres in the second wave of NHS providers of CAR T-cell therapy. NHS England tariffs have been set at a level that is designed to allow appropriate investment in staffing and infrastructure for these complex therapies.
 
Ben Uttenthal, Lead for Immune Effector Cell Therapies, said ‘This is fantastic news for patients in our region, who will now have access to these cutting edge treatments for cancer. We expect to have treated our first NHS patients with CAR T-cell therapy, for high grade B cell lymphoma and acute lymphoblastic leukaemia, before the end of this year. The clinical infrastructure that we are putting in place for this will give a real boost to translational research in cellular immunotherapies here in Cambridge.’

We are pleased to welcome Dr Simon Richardson to the programme. Simon has been awarded a 5-year CRUK Clinician Scientist Fellowship and will be working in Professor Brian Huntly's lab. The focus of the fellowship will be on the role CREBBP in Acute B Lymphoblastic Leukaemia (B-ALL) and, in particular, its role in relapse and chemo-resistance. During the project, Simon will work to generate new mouse models of B-ALL, in parallel with drug development using human cell lines and patient material.

Simon completed his PhD in Professor Tariq Enver’s lab at the UCL Cancer Institute using human pluripotent stem cells modelling the impact of the childhood B-ALL driver mutation ETV6-RUNX1 on human fetal lymphopoiesis. Following his PhD, Simon has been working in Dr Marc Mansour’s lab focussing on adapting next generation sequencing techniques to identify novel non-coding mutations in cytogenetically normal acute myeloid leukaemia.

Many congratulations to Dr Peter Campbell who has been elected as a Fellow of the Academy of Medical Sciences. The award honours scientists whose research has advanced medical science, delivered cutting-edge research discoveries, and produced benefits for patients and wider society. This year 50 Fellows were chosen from 413 candidates. Dr Campbell said “I am delighted to become a Fellow of the Academy of Medical Sciences, it is a great honour to be recognised in this way. However, this award really belongs to my colleagues and collaborators here at the Sanger Institute and worldwide. Cancer is a massively complex interplay of genetic interactions that requires large-scale collaboration across to continents to investigate and analyse. I am grateful to everyone I have worked with over the years, and hope that our work will lay the foundations of understanding that will deliver improved treatment and prevention of this terrible disease.”  Read the full article on the Sanger Institute website.

Image credit: Wellcome Sanger Institute, Genome Research Limited.

Many congratulations to Maurizio Mangolini (Ringshausen group) who was recently awarded the Terry Hamblin prize at the UK CLL Forum. The Terry Hamblin prize was established in 2008 in honour of Professor Terry Hamblin, the founder of the UK CLL Forum. The prize is awarded annually for the best CLL (Chronic Lymphocytic Leukemia) related publication from a UK-based group.  Maurizio was awarded the prize for the paper 'Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia' published in Nature Communications in September 2018 and you can read the full paper on the Nature Communications website. 

Many congratulations to Dr Paolo Gallipoli who has been awarded a 5 year Cancer Research UK Advanced Clinician Scientist Fellowship. This award will allow Paolo to start his independent research programme studying metabolic adaptive responses as a mechanism of resistance to novel therapies across multiple subtypes of acute myeloid leukaemia (AML) at the level of leukaemic stem cell. Paolo's research will use several different techniques including forward genetic screening, proteomic/metabolomic analysis by mass spectrometry, ChIP/RNA sequencing and standard functional in vitro and in vivo assays to understand how changes in cell metabolism provide escape routes to current therapeutics in AML and their link to the establishment of leukaemic transcriptional programme. The main aim is to identify novel therapeutic vulnerabilities that can be targeted therapeutically to prevent the establishment of resistance to therapies in AML.

Programme member Dr Elisa Laurenti took part in a short film project promoting collaborations between Israeli and British researchers working together on BIRAX funded projects.  BIRAX (the Britain Israel Research and Academic Exchange Partnership) is a £10 million initiative of the British Council and British Embassy in Israel in collaboration with the Pears Foundation and the UJIA. You can watch the film here.

An active ingredient in eye drops that were being developed for the treatment of a form of eye disease has shown promise for treating an aggressive form of blood cancer. Scientists at the Wellcome Sanger Institute, University of Cambridge, University of Nottingham and their collaborators have found that this compound, which targets an essential cancer gene, could kill leukaemia cells without harming non-leukemic blood cells. The results, published in Nature Communications reveal a potential new treatment approach for Acute Myeloid Leukaemia (AML), an aggressive blood cancer with a poor prognosis.

Joint leader of the project, programme member Dr George Vassiliou said: 

“We have discovered that inhibiting a key gene with a compound being developed for an eye condition can stop the growth of an aggressive form of acute myeloid leukaemia without harming healthy cells. This shows promise as a potential approach for treating this aggressive leukaemia in humans.”

Read the full press release on the Sanger Insititute's website.

Many congratulations to programme member Dr George Vassiliou who has been awarded an ERC Consolidator Grant. The ERC award (of €2 million) will fund a project to study how mutations in genes involved in RNA splicing can start a process that leads to the development of lethal blood cancers such as the myelodysplastic syndromes and acute myeloid leukaemia. At present we do not understand how these mutated genes drive abnormal growth of cells and why they particularly do so in old, but not in young people. Working this out will help us device new ways to treat and potentially also to prevent the development of these cancers.

On the 19th of November, the UK – Israel and the Dotan Center International Symposium ‘Advances in Research of Haematological Malignancies’ was held at the Felsenstein Medical Research Center on the Rabin-Schneider Medical Campus in Israel. There were four sessions throughout the day focussing on the latest research in the field and presentations were given by Haematological Malignancies programme member Professor Bertie Gottgens and co-programme lead Professor Brian Huntly with the Plenary Lecture delivered by co-programme lead Professor Tony Green. Cellular and Molecular Biology programme member Dr KJ Patel from the MRC Laboratory of Molecular Biology also presented at the symposium.

The symposium attendees are pictured, with Mr David Quarrey, British Ambassador to Israel (centre).

Scientists have developed a successful method to make truly personalised predictions of future disease outcomes for patients with certain types of chronic blood cancers. Researchers including co-programme lead Professor Tony Green and members from the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute, and their collaborators, combined extensive genetic and clinical information to predict the prognosis for patients with myeloproliferative neoplasms. The research also identified eight different genetic subgroups of the disease that link with patterns of clinical disease and patient prognosis. Published in the New England Journal of Medicine, this work could lead to personalised medicine for patients with these blood cancers. It will help doctors identify those patients who are likely to have a very good future outlook, and which patients may benefit from specific treatments or clinical trials.

Blood stem cells produce all blood cell types throughout life, including red blood cells that transport oxygen throughout our body and white blood cells called lymphocytes that help us fight infections. New research using cutting-edge single cell technologies reveals that the regulation of the balance between red and white blood cell production, already occurs within the blood stem cell compartment and not later on as originally thought. In a study published in Nature Communications, the Laurenti Lab identified a novel subtype of long-lived blood stem cells that cannot produce red blood cells, but only produce lymphocytes. This cell type is likely play a role during ageing and in the development of blood cancers, where the production of all mature blood cell types is highly imbalanced.

Research published in Nature has revealed that adult humans have many more blood-creating stem cells in their bone marrow than previously thought, ranging between 50,000 and 200,000 stem cells. Haematological Malignancies Programme researchers based at the Wellcome Sanger Institute and Wellcome – MRC Cambridge Stem Cell Institute developed a new approach for studying stem cells, based on methods used in ecology. Programme member and joint senior author Dr David Kent said: “This new approach is hugely flexible. Not only can we measure how many stem cells exist, we can also see how related they are to each other and what types of blood cells they produce. Applying this technique to samples from patients with blood cancers, we should now be able to learn how single cells outcompete normal cells to expand their numbers and drive a cancer. As the cost of genomic sequencing comes down, it is transforming scientific research such that studies previously thought to be impossibly large, are now becoming routine. It is a very exciting time to be working in this space.”

An international team of researchers have found that patients with Acute Myeloid Leukaemia (AML) had genetic changes in their blood years before they suddenly developed the disease. The study, published in the journal Nature, found that blood tests looking for changes in the DNA code can reveal the roots of AML in healthy people. Haematological Malignancies Programme Member Dr George Vassiliou, one of the joint leaders on the study said: “Our study provides for the first time evidence that we can identify people at risk of developing AML many years before they actually develop this life-threatening disease. We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML. Our aspiration is that one day AML prevention would provide a compelling alternative to treatment.”