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Irish blood cancer research making a real impact

The 59th American Society of Haematology (ASH) Annual Meeting is due to take place from 9-12 December in Atlanta, US, highlighting the latest breakthroughs in haematology.

Important Irish research data is due to be presented at the meeting, gathered by researchers from Blood Cancer Network Ireland (BCNI).

BCNI is a collaborative network of clinicians, scientists and population health experts with a shared interest in blood cancer research. The network was established by the Irish Cancer Society and Science Foundation Ireland in 2015 to provide blood cancer patients across Ireland with improved access to novel drugs and treatments through early-stage clinical trials.

Clinical research facilities include NUI Galway, University College Cork, and in Dublin, St James’s Hospital/Trinity College Dublin, Beaumont Hospital, and the Mater Hospital.  Cancer Trials Ireland (CTI) is working in partnership with the national network.

Recently, it was announced that researchers from NUI Galway’s Regenerative Medicine Institute (REMEDI) and Advanced Glycoscience Research Cluster (AGRC) have been working together to examine how sugar (carbohydrate) molecules attached to the surfaces of immune cells participate in the normal protective functions of those cells. The research shows that chains of sugar molecules, referred to as glycans, attached to proteins and other components of the cell surface, play an essential role in the function of two very important cells of the immune system: T-cells and dendritic cells.

“I am very excited about these results regarding the restoration to immunity after removal of sugar residues on antigen-presenting cells. I am currently working with Prof Thomas Ritter and Dr Aideen Ryan [from REMEDI] to investigate the role of glycans in the immune response to blood cancer. The exciting findings of this work, which show that the manipulation of sugar residues on mesenchymal stromal cells (MSCs) helps to restore anti-cancer immune response, will be presented at the annual meeting of the ASH,” BCNI Director Prof Michael O’Dwyer commented.

Other BCNI-related research to be presented at the ASH meeting will highlight the relationship of sialic acid and multiple myeloma, as well as clinical trial data on cyclophosphamide and daratumumab to treat the disease.

Regarding the former, Prof O’Dwyer told the Medical Independent that sialic acid is a non-energy type of sugar normally expressed on the surface of many cells in the body and on the surface of cells. The sugar coating of proteins and lipids on the surface of cells can greatly influence the function of these proteins. There are receptors on immune cells called siglecs (sialic acid-binding immunoglobulin-like lectins), which bind to sialic acid, which leads to an inhibitory signal into the immune cell. Siglecs are analogous to PD-1 receptors that can be expressed on T-cells.

“So, for example, if this is a natural killer cell, then instead of becoming activated, the natural killer cell is inhibited, therefore by expressing lots of sialic acid the tumour cell can effectively evade killing by the natural killer cells,” Prof O’Dwyer explained.

“This is one particular example and my group now have data that this may be the case with multiple myeloma as well, and we will be presenting this data at the upcoming ASH meeting in Atlanta.”

Prof O’Dwyer added the research collaboration he is involved in has also shown how sialic acid plays an important immunosuppressive role in the context of MSCs found in bone marrow, which are important for making and repairing skeletal tissues such as cartilage, bone and the fat found in bone marrow.

“We have taken MSCs and treated them with the same inflammatory stimuli typical of cancer patients and found that this causes an increase in the sugars of the MSCs and makes them much more immune-suppressive than they had been previously,” he outlined.

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Prof Michael O’Dwyer, Director, BCNI

Reversing effects

“What is really nice is that we can then use a specific drug that blocks the incorporation of these sugars onto the surface of the MSC and this completely reverses the effects, so the MSCs can no longer block the activation of the immune system.”

Other exciting research to be presented at the meeting relates to the combination of cyclophosphamide and daratumumab (DARA) in treating multiple myeloma.

This innovative phase 1 clinical trial, being pioneered by BCNI researchers in collaboration with CTI, investigates for the first time whether the addition of a new multiple myeloma treatment, DARA, to standard-care chemotherapy containing the drugs cyclophosphamide and bortezomib is beneficial for treating newly-diagnosed patients.

Prof O’Dwyer said: “This is the first trial to combine cyclophosphamide and daratumumab and we have generated very nice data, which will be presented at ASH, that cyclophosphamide is able not only in vitro, but also within patients, to activate the macrophages, enabling them to better kill myeloma cells once they have been treated with daratumumab.”

Macrophages are potentially a very important effector cell to enable killing of tumours that have been treated with monoclonal antibodies. The new data suggests that while for most myeloma patients, macrophages may not be activated or contribute to the killing of tumours in daratumumab-treated patients, “when you add in cyclophosphamide, this now engages the macrophages and allows them to make an important contribution to the cytotoxic activity of the antibody”.

Exciting time

All in all, Prof O’Dwyer said it is an exciting time for research in blood cancer in Ireland as a result of advances made by the BCNI.

 “We have a small number of studies [currently],” he acknowledged.

“In terms of the numbers of patients who have enrolled, to be honest, they are not huge. At the same time, it is early days and we are showing what we are capable of and the quality of data we are capable of producing and how this can make an important contribution to international research.”

He also noted that while multiple myeloma remains non-curative for most patients, research breakthroughs are giving more hope to patients than ever before.

“I think we still generally say it is an incurable condition but having said that, increasingly we do recognise a small proportion of patients who get treated with intensive therapy may enjoy lasting remissions,” Prof O’Dwyer said.

“With current therapy, we are probably ‘curing’ about 15 per cent of our patients, but it is not a high enough figure that when you see a patient, you can really make any promises about curing them. I think we would need to get that figure significantly higher in the future to really talk about having approaches that are curative. What is clear is the deeper the response we can achieve with our treatments, the more likely those responses will translate into durable, lasting responses. Potentially, the incorporation of daratumumab to frontline treatment may enable this.”

Promising treatments for leukaemia

Cancer Trials Ireland (CTI) recently announced the opening of the Irish arm of an international cancer trial that is investigating promising cures for leukaemia.

It is expected that up to 60 patients from Ireland with chronic lymphocytic leukaemia (CLL) will participate in the trial.

The trial is open in Cork University Hospital, University Hospital Waterford, University Hospital Galway, and in Dublin, St James’s University Hospital, the Mater Hospital and Beaumont Hospital.

The trial aims to test treatments for leukaemia that could be more effective and have fewer side-effects than standard chemotherapy treatments.

CLL is the most common type of leukaemia in the Western world, with most cases developing in people aged over 55 years. About 200 people in Ireland are diagnosed each year with CLL, which affects the blood, lymph glands and bone marrow.

The international trial is being led by the German CLL Study Group (GCLLSG). This group is the world’s leading authority on CLL research.

Prof Patrick Thornton, Consultant Haematologist at Beaumont Hospital, who has collaborated with the GCLLSG on previous trials, is the Chief Investigator for the trial in Ireland. The trial is being co-ordinated by CTI.

“Chemoimmunotherapy is the standard initial (first-line) treatment for patients with CLL and with it, many patients can achieve good remissions. Unfortunately, it can be too toxic for some patients because they can be less fit and unable to tolerate intensive regimens. So there is a pressing need for alternative chemotherapy-free treatments,” Prof Thornton said.

“In this trial we are testing a number of oral non-chemo treatments and new antibodies which have proven to be effective and safe as second-line treatments, with little side-effects.

“We’ll determine which treatment is more effective and has fewer side-effects than the standard chemoimmunotherapy,” he said.

“This is a very significant trial because of the positive results the treatments we’ll be comparing have already achieved and its size, in terms of the number of countries, research units and patients participating. I’m confident it will deliver a new standard of care,” Prof Thornton said.

Almost 1,000 patients from 160 research units across 10 countries will participate in the trial. Participating countries include Ireland, Austria, Belgium, Denmark, Germany, Finland, Israel, the Netherlands, Sweden and Switzerland. Patients will be on the trial for up to five years.

“To be invited to open a trial of this significance in Ireland is a great vote of confidence in Ireland’s cancer trials research community and our ability to contribute to the global effort to find answers to cancer,” Prof Thornton commented.

“Not only does it help us contribute our expertise to finding better treatments, it enables our patients to access promising treatments at no cost, which they would otherwise not be able to access for many years.”

The trial will compare the current standard chemoimmunotherapy treatment for physically fit patients with CLL (chemoimmunotherapy with either fludarabine plus cyclophosphamide plus rituximab (FCR) or bendamustine plus rituximab (BR)) with three new and different combinations of drugs (obinutuzumab, ibrutinib and venetoclax) as a first-line treatment.

There is also a translational dimension to the trial, as it will look at the modern molecular markers, for example NOTCH1, which effect treatment response and remission duration and survival.

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