MPN AA Fellowship: Engineering and Pre-Clinical Validation of CALR+ directed CAR-T cells

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Dr Chloe Thompson-Peach (R) accepting the cheque from the MPN AA’s Jolanda Visser

MPN AA is thrilled to announce the grant of $30,000 for an MPN Alliance Australia Fellowship titled Engineering and Pre-Clinical Validation of CALR+ directed CAR-T cells.  The grant has been made to an early career researcher from the South Australian Health and Medical Research Institute (SAHMRI) and the University of Adelaide, Dr Chloe Thompson-Peach. Chloe has previously been part of the team under Dr Daniel Thomas researching MPNs in Adelaide at SAHMRI (see separate story).  The fellowship will last for a year, and we will update you during that time.

The grant has been made possible by a generous donation of funds from a Sydney MPN patient, Sarah Gardner, following her recent fund raiser.
We are extremely grateful to Sarah for making the Fellowship grant possible and to the Leukaemia Foundation for facilitating provision of the grant. For Chloe, it enables her to pursue her research passion which has the potential to improve lives of MPN patients into the future.

Sarah Gardner. Sarah’s fund raising efforts have made this MPN Fellowship possible

Research aims for the project – Dr Chloe Thompson-Peach

Myelofibrosis is an insidious condition of the bone marrow, which disrupts the normal production of blood cells. It is characterised by painful inflammation, low blood counts and fibrous tissue building up in the bone marrow. In some patients, myelofibrosis can also develop into acute leukaemia over time. The lack of effective therapeutic options for these cancers has led us to the development of a new immune treatment for these individuals. We have developed a novel immune treatment, a biological therapy, that is a monoclonal antibody directed against the mutant CALR gene, which the second most common cause of myelofibrosis or essential thrombocythemia. We have shown this to be effective in cell lines and patient cells harbouring pathogenic CALR mutations in the laboratory. Additionally, our treatment has also been shown to have no effect on cell lines and primary cells that do not carry mutations within the CALR gene, suggesting it is truly selective, which means it will not have side effects.

In this fellowship, I propose to make and test a specific “CAR” T cell for these patients, a chimeric antigen receptor T cell, using the knowledge we have gained from our antibody therapy. CAR T cells involves removing the good white cells from a patient’s blood and then inserting the CAR gene into these T cells in the lab. These cells are then reprogrammed to target the mutated CALR protein on the surface of the cancer cells. These cells will initially be tested in mouse models of CALR driven myelofibrosis to determine if the CALR specific CAR T cells are able to seek out and destroy cells carrying the pathogenic CALR mutation. I am hopeful that by combining antibody therapy, interferon therapy and specifically designed CAR T cell we may move towards demonstration of long-term remission or cure in patients with myelofibrosis.

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Leukaemia Foundation’s July MPN newsletter

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The Leukaemia Foundation has released its latest newsletter for MPN patients and it’s an excellent read.
There is so much happening in the MPN space in Australia.
Individual links to each story in the July newsletter are provided below.

1.  A tool predicting the potential progression of MPNs is something under development from Professor Wendy Erber, a world leading diagnostic haematologist and MPN specialist, and her team of dedicated researchers.

2.   An antibody for myelofibrosis – “that’s a true discovery”
A new monoclonal antibody discovered by Adelaide researchers could become the world’s first effective treatment for primary myelofibrosis.

3.   Expert interview with Dr Cameron Curley on transplantation and CAR-T therapy.

4.  Patient stories 

–  Living with PV has become “a normal way of life” for Debbie

–  Charlie’s blood cancer went undiagnosed for a decade

5.    Clinical trial comparing allogeneic stem cell transplants vs best available non-transplant therapies for myelofibrosis (MF).
Associate Professor Nada Hamad is the Australian lead on this international trial which will compare best available non-transplant therapies with stem cell transplant for MF patients.

6.    Optimal care pathways being developed for blood cancer patients.

7.   WEBINAR: Exploring real life with blood cancer: The mind and body experience

This is a brilliant webinar, packed full of valuable advice featuring:
–  haematologist Dr Cecily Forsyth
–  psychologist Jane Fletcher
–  physiotherapist Julie Allen

8.   PODCAST: Talking Blood Cancer podcast series from the Leukaemia Foundation has been a great success and is filling a need for people living with blood cancer.

9.   More MPN stories from this and earlier newsletters are available

10.  Need support?
The Leukaemia Foundation encourages you to find out about the different ways they can help
– by visiting their  website or
– by calling 1800 620 420 to speak with a Blood Cancer Support Coordinator.

 

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MPNs and fatigue

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Ken Young, a founding member of the MPN AA and well known to the Australian MPN community, has co-authored an article about how fatigue can be a problem for MPN patients.
The research surveyed 90 patients who had already identified as suffering fatigue. Researchers then undertook qualitative research with those MPN patients and 23 were interviewed in considerable depth. The level of fatigue appeared to be more marked in patients with myelofibrosis.

The authors concluded that ‘health professionals could affect patients’ lives substantially by acknowledging and understanding fatigue in MPN, including contributing factors and potential opportunities for management.’  The article also proposed that ‘More systematic data describing the causes and management of MPN fatigue is needed.’

The full article is available HERE.

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MPN mutations – further research showing they are often acquired in utero or early childhood

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This year has seen two significant bodies of work published about the timing of the acquisition of blood cancer mutations in patients with myeloproliferative neoplasms (MPNs).
These findings lend further support to earlier research that, in many cases, these mutations occurred in utero or early childhood. They also have broader implications for cancer patients.

1. The first paper, ‘Life histories of myeloproliferative neoplasms inferred from phylogenies’ was published in Nature 19 January 2022, by researchers from the Wellcome Sanger Institute and the University of Cambridge.
Researchers found that mutations that cause MPNs have been traced to acquisition in childhood or even in utero, suggesting that cancer causing events can arise in early life and grow over decades before leading to symptoms.  This research further suggests that these mutations will cause blood cells to multiply at different rates in different people, and those in whom these mutations cause faster growth have cancer symptoms appearing earlier. If these mutations proliferate slowly, it is possible that the cancer symptoms would never appear, or be noticed after death by other causes.

Leading MPN researcher and haematologist Jyoti Nangalia, a senior author on the study and who also earlier discovered the CalR mutation in MPNs, advised that ‘This is not something we were expecting. Blood cancer impacts thousands of lives every day and research such as ours into the timing and pace of how different cancers develop is crucial if we are going to find new ways to prevent these conditions. The success of our approach for tracking the origin and growth of this blood cancer could be applied to many other cancers and diseases.’

Further work is now needed to understand how this information could help predict cancer risk in people with these mutations. In addition to early detection, research is also needed into whether current treatments or new therapies could be used to slow or prevent the development of cancer once a person is identified as ‘at risk’.

This is ground-breaking work for MPN patients.  A summary of the findings is available HERE.

2. The second body of work is titled ‘In utero origin of myelofibrosis presenting in adult monozygotic twins‘

This research from a team of Oxford researchers which included lead MPN researcher and haematologist Adam Mead, identified three patients presenting in their 30s with an MPN who had acquired their initiating somatic driver mutation by a single cell in utero.
The paper describes a case of monozygotic twins presenting with CALR mutation-positive primary myelofibrosis when aged 37 and 38 years. Researchers were able to determine that the CALR mutation was a somatic acquisition, not germline. Their whole-genome sequencing lineage tracing revealed a common clonal origin of the CALR-mutant MPN clone, which occurred in utero followed by twin-to-twin transplacental transmission and subsequent similar disease latency. Hematopoietic stem cells (HSCs) were identified as the likely MPN-propagating cell.

A third patient in the study presented with polycythemia at 34 years. A neonatal blood spot analysis confirmed in utero origin of the JAK2V617F mutation.
These findings provide a unique window into the prolonged evolutionary dynamics of MPNs and fitness advantage exerted by MPN-associated driver mutations in HSCs.

A link to the full paper is not paywalled and is available in Nature Medicine ‘In utero origin of myelofibrosis presenting in adult monozygotic twins’.

 

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Promising future for MF targeted therapies

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A review article dated 2 May 2022 in the American Cancer Society Journal ‘Cancer’ titled ‘Defining disease modification in myelofibrosis in the era of targeted therapy’ has outlined a promising way forward for myelofibrosis (MF) targeted therapies.

The authors are several renowned MPN specialists from around the world and their article refers to ‘exciting developments’. Their conclusions are extremely encouraging for all MPN patients.

Currently, the only cure for MF is an allogeneic stem cell transplant and treatment criteria for MF have mainly focussed on relieving symptoms rather than survival benefit.  However in this review article, the authors outline several promising clinical trials able to modify the disease course in MF.  While these trials have had relatively small patient numbers, the authors’ view is that the treatment landscape for MF is ‘set to evolve rapidly as understanding of the molecular pathogenesis of MF sheds light on novel therapeutic targets and the possibility of selectively depleting the malignant HSC compartment.’

The article concludes:
‘In summary, the possibility of disease modification has the potential to revolutionize clinical practice and treatment decision-making for patients with MF. As novel end points begin to emerge, it will be important to re-evaluate clinical trial designs, and potentially redefine disease modification, adding new end points to survival outcomes, to ensure the true potential for disease modification and MF therapy is realized. Standardized definitions and assessments are needed across clinical trials, along with the inclusion of patients with newly diagnosed disease, where the greater potential for disease modification may lie.’

The full article is unlocked and able to be read HERE.

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Myelofibrosis treatments – real world findings from the UK

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Some of the UK’s leading MPN haematologists have published results of a retrospective real-world study of current treatment pathways for myelofibrosis (MF) in the United Kingdom.
The study is published in the Journal ‘Therapeutic Advances in Hematology’.

The abstract summary explains:
‘These results provide insight into real-world clinical practice for patients with MF in the United Kingdom. Despite the known high prevalence of disease-associated symptoms in MF, symptoms were poorly documented. Most patients were initially observed or received hydroxycarbamide, and ruxolitinib was used as first-line management strategy in only a minority of patients.’
And, further…..

‘The results of this study suggest that medical records can be missing key information, which is needed to decide which is the best way to treat a patient with myelofibrosis. They also suggest that clinicians in the UK prefer observation to treatment for a large number of patients with myelofibrosis. This could mean that the approach used for many patients with myelofibrosis does not help them to control symptoms that have an impact on their daily lives.’

The full paper is available HERE.

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Promising finding for possible future myelofibrosis treatment

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Adelaide researchers have discovered a possible new method to treat myelofibrosis (MF), that could have the potential to greatly extend lifespan without the side effects caused by current treatments.

While MF symptoms can often be controlled with the drug Ruxolitinib, side effects may be problematic and currently, the only cure for MF is an allogeneic stem cell transplant.

Dr Daniel Thomas, leader of the Myeloid Metabolism Lab at the South Australian Health and Medical Research Institute, (SAHMRI) and Associate Professor of Medicine at the University of Adelaide, led the study in collaboration with Professor Angel Lopez at SA Pathology.

Dr Thomas says it was a stroke of luck that led to the extraordinary find.
“We were actually trying to make a tool to study myelofibrosis. We didn’t realise the antibody we made would have therapeutic properties,” Dr Thomas said.
“Our drug blocked the growth of cancer cells in a very aggressive live model of the disease, significantly increasing survival rate without noticeable negative side effects,” Dr Thomas said.

Co-lead author and biochemist Dr Denis Tvorogov generated antibodies using a peptide fragment called ‘neoepitope’ that’s only present within the cancer and not on any normal tissues. What he didn’t expect was for the antibody to kill cancer cells when he tested it on patient samples, working with an early career scientist Dr Chloe Thompson-Peach.
“What is really exciting is that many other cancers have similar peptide fragments that we could also target by harnessing the immune system,” Dr Tvorogov said.
“These fragments are created by the insertion or deletion mutations within the cancer. We’ve found they not only drive cancer growth but also vulnerable for targeting without side effects.”

The new antibody is currently being prepared for early phase clinical trials set to run in South Australia later this year, supported by local biotech company, AusHealth.  Pre-clinical models have shown the drug is effective at shrinking tumours and Dr Thomas is confident the antibodies will prove to be safe and effective in humans.
“We estimate there are at least 12,000 Australians living with cancer or having had cancer that express a recurrent neoepitope similar to what is found in myelofibrosis, that could be curable with
an immunotherapeutic approach,” Dr Thomas said.

“This discovery brings us a fresh perspective. We need to build cell therapies and antibody therapies against these fragments as fast as possible.”

The full media release is available:  SAHMRI media release – Lucky find could hold key to beating rare blood cancer —

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World rare disease day

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Today is RARE DISEASE DAY.

MPN expert, clinician scientist Professor Andrew Perkins, is interviewed about his team’s work on MPNs HERE.

WATCH MPN expert Professor Andrew Perkins and the MPNAA’s Ken Young speaking about MPNs.

 

 

 

 

 

 

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Momelotinib: an emerging treatment for myelofibrosis patients with anaemia

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A phase 3 clinical trial has been underway for myelofibrosis patients who are symptomatic, suffer from anaemia and have been previously treated with a Jak inhibitor. The trial was using the drug Momelotinib.

Findings just released on 25 January this year are very encouraging.  Momelotinib achieved statistically significant benefit on symptoms, anaemia and spleen size.
The trial, undertaken by drug company Sierra Oncology, is a global, randomized, double-blind clinical trial evaluating momelotinib in 195 myelofibrosis patients.

Access to the full report of the trial is available HERE. The full data set will be presented at an upcoming medical meeting which we will also publish once available.

Ruben Mesa, MPN specialist  and co-principal investigator of the study said that “As a clinician, I am thrilled to see data that confirm the potential of momelotinib as a treatment option for myelofibrosis patients who are anaemic or at risk of becoming anaemic,”  “Anaemia of myelofibrosis is strongly correlated with reduced quality of life and a decrease in overall survival. Half of all myelofibrosis patients present with anaemia at diagnosis and virtually all become anaemic over time. With currently approved therapies being myelosuppressive, it’s wonderful to know that we may soon have such an effective treatment option for these patients.”

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Second versus first wave of COVID in MPN patients

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European haematologists have been undertaking ongoing studies of MPN patients who have contracted COVID.  This study covers the second COVID wave of 304 MPN COVID cases from 39 different hematology centres.  Their findings are outlined in just released (January 2022) correspondence in the International Journal ‘Leukemia’.  Importantly, they found a relatively higher risk from COVID for patients over 70, more thromboses in ET patients and a need for permanent surveillance of MPN patients who have survived the acute phase of a COVID infection.

‘Patients of the second wave presented, compared to those of the first, with a less severe disease, including a lower degree of inflammation, leading to hospitalization in a smaller percentage of cases. Overall, the mortality rate was significantly lower, likely due to early COVID-19 diagnosis, facilitated by the greater availability of swabs than in the first wave, more efficient management of infected patients, better prepared health systems and preferential protection of older and higher-risk MPN vulnerable subjects.’

‘However, patients over 70 years still presented with an excess of mortality, particularly when associated with comorbidities and an MF phenotype. Unfortunately, no data are available so far in our series to support a role of vaccinations. The high thrombosis rate in patients with ET was confirmed, suggesting that in this MPN phenotype regimens of antithrombotic prophylaxis in addition to heparin should be explored. Also in the second wave, but to a lesser extent than in the first, the health consequences of COVID-19 protracted far beyond acute infection, suggesting careful and permanent surveillance of patients with MPN who have survived the acute phase of SARS-CoV-2 virus infection.’

The full article has been made available HERE.

 

 

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