Myeloproliferative neoplasms (MPNs) are a group of chronic blood cancers that begin when a mutation arises in a blood stem cell. Over time, some patients develop myelofibrosis, a serious condition in which scarring of the bone marrow disrupts normal blood production and can lead to anaemia.
In roughly one in five cases, the disease progresses into an aggressive leukaemia-like phase where survival may be measured in months. For most patients, there are no curative treatments available, although current therapies can help control symptoms and slow disease progression. For a minority of patients, bone marrow transplantation can be curative, but carries substantial risks.
A new study led by researchers at UCL and the University of Oxford has developed a CAR T cell therapy designed to target cancer-driving stem cells in MPNs while leaving healthy blood cells unharmed. The study, published in Science Translational Medicine, focuses on mutations in CALR, which are found in around a third of patients with MPNs.
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 for some other blood cancers. In this study, the researchers designed CAR T cells to recognise an abnormal protein produced by mutant CALR. This protein appears on the surface of cancer stem cells, providing a visible marker that can be targeted by the immune system.
Using patient samples, and laboratory models that recreate human bone marrow, the team showed that the engineered CAR T cells could selectively kill cells carrying the mutation without harming other blood cells.
The team also tested the CAR T cells in lab-grown 3D mini bone marrows. With the bone marrow model seeded with real myelofibrosis cells, the team were able to show that the CAR T cells could move into heavily scarred tissue (fibrosis) and kill the cancer cells, suggesting that the approach may be able to work even in the challenging environment of myelofibrosis.
Professor Beth Psaila, from the Ludwig Institute for Cancer Research and the Weatherall Institute of Molecular Medicine, 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 team is currently seeking funding for a Phase I clinical trial is being planned at UCLH, and hope that if successful in clinical trials, CALR-targeted CAR T cell therapy could provide a new treatment option for patients with this subset of myeloproliferative neoplasms.