Ludwig Link readers might recall that the Oxford Branch, in collaboration with colleagues at the University of Oxford, launched a Program on Myeloproliferative Neoplasms (MPNs) in 2025 focused on developing new approaches to treating, diagnosing and assessing risk for MPNs. The first research partially supported by the Program was published in Science Translational Medicine in July. MPNs are slow-growing blood cancers. Over time, about a third of patients progress to a stage called myelofibrosis—where extensive scarring of the bone marrow develops—at which point the median life expectancy is 5-7 years. One in five of these patients progress further to an aggressive and incurable leukemia known as blast-phase (BP) MPN. About a third of MPNs are driven by mutations to the chaperone protein calreticulin (CALR). In these cases, the mutant CALR protein binds to the thrombopoietin receptor (TpoR), migrating to the cell membrane and aberrantly activating TpoR signaling in blood stem cells and megakaryocytes. Spotting an opportunity in that phenomenon, Ludwig Oxford’s Bethan Psaila collaborated with Alexandros Rampotas and Martin Pule’s lab at University College London to design a CAR-T cell to target the cell-surface mutant CALR-TpoR complex. They showed using samples from myelofibrosis patients that their CAR-T cells selectively killed mutant stem cells while sparing healthy ones and demonstrated in orthotopic mouse models of mutant CALR+ leukemia that they could also improve survival. In an organoid model of myelofibrotic marrow, the CAR-T cells efficiently infiltrated densely fibrotic tissue to kill their quarry. However, the CAR-T cell therapy worked less well on samples from patients with BP-MPN due to the relatively low levels of CALR expressed on target cells. This was disappointing, as these patients have the greatest need for more effective therapies. To address this challenge, the team developed an innovative strategy to boost CAR-T cell targeting of mutant cells in patients with BP-MPN: pretreatment with a TpoR agonist therapy. This novel immunotherapy represents a promising new strategy to more effectively treat malignancies driven by mutant CALR.
CAR T cell therapy selectively depletes disease-driving mutant calreticulin cells in xenotransplants and human organoid models of myelofibrosis
Science Translational Medicine, 2026 July 1