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Alexandros Rampotas: Targeting Mutant CALR With Precision CAR-T Therapy
Alexandros Rampotas/LinkedIn
Jul 3, 2026, 18:24

Alexandros Rampotas: Targeting Mutant CALR With Precision CAR-T Therapy

Alexandros Rampotas, Academic Clinical Lecturer in Haematology at UCL Cancer Institute, shared on LinkedIn about a recent article he and his colleagues co-authored, published in Science Translational Medicine, adding:

“Proud to share that our work is published today in Science Translational Medicine.

Myelofibrosis and related myeloproliferative neoplasms (MPNs) remain largely incurable.

Around a quarter are driven by mutations in CALR, and while JAK inhibitors and cytoreductive agents can control symptoms, none selectively targets the malignant stem cells at the root of the disease. There is a real unmet need for a therapy that does.

Every pathogenic CALR mutation converges on the same altered C-terminus, which binds the thrombopoietin receptor (TpoR) and is displayed on the surface of disease-driving cells — a genuine cancer neoantigen.

We raised an scFv (RPG4) against that mutant epitope and engineered it into a CAR-T cell that only recognises cells co-expressing mutCALR and TpoR.

Some of the key findings:

  • Selective depletion of mutant stem/progenitor cells from patient samples (60–75% killing), with no off-target activity against JAK2-mutant or healthy cells. VAF correlation an scRNA data indicate that this reflects up to 100% elimination of the malignant clone without affecting the normal stem cell/progenitor cells that survive.
  • 96.7% clearance of mutCALR+ cells even when they made up just 10% of the mixture
  • Retained potency inside a fibrotic, immunosuppressive marrow microenvironment — modelled in a human iPSC-derived bone marrow organoid
  • More than doubled survival in in vivo leukaemia xenograft models
  • A strategy using the TpoR agonist eltrombopag to boost target expression and restore killing in aggressive blast-phase disease

Alongside the therapy, we advanced a human bone marrow organoid (‘chimeroid’) platform that lets us evaluate blood-cancer immunotherapies in a realistic human tissueenvironment — something we hope will be useful well beyond MPNs.

Importantly, this is now moving towards patients: we are planning a first-in-human Phase I clinical trial, CAL-STRIKE, to bring this therapy into the clinic.

Sincere thanks to my co-authors and collaborators across UCL Cancer Institute, MRC Weatherall Institute of Molecular Medicine and our funders Blood Cancer UK and Medical Research Council — particularly Zoë Wong, Isaac Gannon and senior authors Claire Roddie, Beth Psaila and Martin Pule.

A true team effort.”

Title: CAR T cell therapy selectively depletes disease-driving mutant calreticulin cells in xenotransplants and human organoid models of myelofibrosis

Authors: Alexandros Rampotas, Zoë C. Wong, Isaac Gannon, Charlotte K. Brierley, Yuqi Shen, Camelia Benlabiod, Ashlyn Chee, Saif Khan, Nawshad Hayder, Gordon Weng-Kit Cheung, Marina Mitsikakou, Eleanor Murphy, Mathieu Ferrari, Anna Bulek, Antonio Rodriguez-Romera, Lauren Murphy, Aude-Anais Olijnik, Manuel Rodriguez-Justo, Caroline Marty, Ian Hitchcock, Daniel Royston, Adam J. Mead, Abdullah O. Khan, Jonathan Lambert, Claire Roddie, Bethan Psaila, Martin A. Pule Alexandros Rampotas: Targeting Mutant CALR With Precision CAR-T Therapy

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Abdullah O. Khan Adam J. Mead Alexandros Rampotas Anna Bulek Antonio Rodriguez-Romera Ashlyn Chee Aude-Anais Olijnik Bethan Psaila Camelia Benlabiod Caroline Marty Charlotte K. Brierley Claire Roddie Daniel Royston Eleanor Murphy Gordon Weng-Kit Cheung Health Hematology Hemostasis Hemostasis News Hemostasis Today Ian Hitchcock Isaac Gannon Jonathan Lambert Lauren Murphy Manuel Rodriguez-Justo Marina Mitsikakou Martin A. Pule Mathieu Ferrari Nawshad Hayder Saif Khan Yuqi Shen Zoë C. Wong
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