©
DrawImpacts
MPNs are chronic blood cancers that begin when a mutation arises in the DNA of a blood stem cell. In one in three patients, the disease progresses to an advanced phase called myelofibrosis, where the bone marrow becomes scarred and unable to produce healthy blood. Rarely, MPN can transform to a leukaemia-like phase, where survival may be measured in months. For most patients, there are no curative treatments available.
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 recognise 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 engineered CAR T-cells showed they could precisely kill cancer cells carrying the CALR mutation, without harming other blood cells.
When the team tested their research using lab-grown 3D mini bone marrows seeded with real myelofibrosis cells, they were able to show that the CAR T cells were even able to move into heavily scarred tissue (fibrosis) and kill the cancer cells.
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:
Our model is designed to recreate the real conditions in which these cancers grow, including the fibrosis and complex tissue structure that might present a challenge for treatments that depend on immune cells working. Seeing the CAR T cells find and kill the cancer cells in fibrotic marrow organoids was a highly encouraging step and gives us additional hope that this therapy may work in patients.
We hope this platform will speed up the development of safer, more effective immunotherapies for myelofibrosis and other blood cancers.
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), and around a third of these cases are trigged by mutations in CALR, with many more people already living with the disease.
The team is currently seeking funding for a planned first-in-human clinical trial, and hopes that if early clinical results are encouraging, wider access to this potentially transformative treatment will follow.
Read the full paper in Science Translational Medicine here: CAR T cell therapy selectively depletes disease-driving mutant calreticulin cells in xenotransplants and human organoid models of myelofibrosis