CAR T cell therapy targets key mutation driving rare blood cancers
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A new form of CAR T-cell therapy has been designed to find and destroy the cancer-driving stem cells responsible for a group of blood cancers known as myeloproliferative neoplasms (MPNs), while leaving healthy blood cells unharmed, according to new research led by UCL and University of Oxford researchers.
MPNs are chronic blood cancers that begin when a mutation arises in the DNA of a blood stem cell. Over time, some patients progress to myelofibrosis, a serious condition marked by scarring of the bone marrow and anemia.
In roughly 1 in 5 cases, the disease transforms into an aggressive leukemia-like phase where survival may be measured in months. For most patients, there are no curative treatments available.
A precise target in CALR
CAR T-cell therapy works by reprogramming a patient's own immune cells to target specific cells in the body and is already a successful treatment in other blood cancers. In this study, published in Science Translational Medicine, the engineered cells were designed to recognize a mutation found in around a third of MPN patients called CALR.
Using patient samples, a model that recreates human bone marrow in the lab and studies in mice, the CAR T cells showed they could precisely kill cancer cells carrying the CALR mutation without harming other blood cells.
A Phase I clinical trial is being planned at UCLH, with the aim of beginning within the next one to two years, subject to funding and regulatory approval.
First author Dr. Alex Rampotas (UCL Cancer Institute) said, "MPNs can be devastating, especially once they progress to myelofibrosis, and current drugs often don't remove the cancer stem cells that are driving the disease. What's exciting about this approach is its precision: The CALR mutation creates an abnormal protein on the surface of these cells, giving us a clear target.
"CAR T-cell therapy technology can exploit this vulnerability, turbo-boosting the immune system to eradicate those cells and allow normal blood production to recover.
"Our ambition is to turn this into a first-in-human trial and, ultimately, a treatment that can selectively eliminate the root of the disease. If successful, it could offer patients a route beyond symptom control toward deeper, longer-lasting remissions, with the hope of restoring healthy blood production."
Limits of current care
Current treatments for MPNs include JAK inhibitor drugs, which can calm overactive immune responses and slow disease progression, but they don't remove the cancer stem cells that keep the disease going. Most patients eventually stop responding to these drugs.
A bone marrow transplant can be curative, but it is suitable for only a small minority of patients and can carry up to 40% treatment-related mortality.
Testing in scarred marrow
The CALR mutation can be found on the surface of the cancer stem cells, acting like a visible flag that the immune system can potentially recognize. The team engineered CAR T cells to detect this flag, enabling them to kill CALR cancer cells with high potency and selectivity.
For patients whose disease had progressed to an accelerated phase, the CAR T cells initially worked less well because the target protein levels were lower. The researchers found that eltrombopag (a drug used clinically for some platelet and blood conditions) could increase the amount of the target on cancer cells, improving CAR T-cell killing.
The team also tested its research using lab-grown 3D mini bone marrows. With the bone marrow model seeded with real myelofibrosis cells, the team was able to show that the CAR T cells could move into heavily scarred tissue (fibrosis) and kill the cancer cells.
In a mouse model, the CALR-targeting CAR T cells also controlled leukemia growth and significantly prolonged survival.
One of the senior authors on the study, Professor Beth Psaila, from the MRC Weatherall Institute of Molecular Medicine and Ludwig Institute for Cancer Research, University of Oxford, said, "Our model is designed to recreate the real conditions these cancers grow in, including the fibrosis and complex tissue structure that can make treatments fail in the lab-to-clinic gap. Seeing the CAR T cells find and kill the cancer cells in fibrotic marrow organoids was a highly encouraging step.
"Just as importantly, the model lets us test not only whether a therapy works, but how it works, cell by cell, in human tissue. We hope this platform will speed up the development of safer, more effective immunotherapies for myelofibrosis and other blood cancers."
The path to a trial
MPNs are classed as rare, but around 4,000 people are diagnosed with an MPN in the UK each year (about 8 in every 100,000 people). The CALR-mutated group represents around a third of cases, or around 600–900 newly diagnosed patients a year, with many more people already living with the disease.
The team is currently seeking funding for the planned clinical trial and is working with the MHRA on the regulatory pathway. Researchers predict that if early clinical results are encouraging, wider access to the potentially transformative treatment could follow in the early-to-mid 2030s.
Publication details
Alexandros Rampotas et al, CAR T cell therapy selectively depletes disease-driving mutant calreticulin cells in xenotransplants and human organoid models of myelofibrosis, Science Translational Medicine (2026). DOI: 10.1126/scitranslmed.adz3553. www.science.org/doi/10.1126/scitranslmed.adz3553
Journal information: Science Translational Medicine
Key medical concepts
Myeloproliferative DisordersMyelofibrosis
Clinical categories
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