VJHemOnc Podcast

Targeting mutant CALR in MPNs with antibodies & cellular therapy: the potential for disease modification

Jul 14, 2025
This conversation features Claire Harrison, a haematologist with expertise in MPNs, Alex Rampotas, a clinician-researcher focused on CAR-T therapies, Jean-Jacques Kiladjian, a hematologist with a deep understanding of MPN biology, and John Mascarenhas, involved in MPN clinical trials. They explore the potential of targeting mutant CALR in MPNs. Key insights include the promising early results of the INCA33989 trial, the development of CAR-T therapies aimed at mutant CALR, and innovative approaches using organoid models to test immunotherapies effectively.
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INSIGHT

MutCALR Is A Surface Neoantigen

  • Mutant calreticulin (mutCALR) is uniquely targetable because it traffics to the cell surface while wild-type forms remain intracellular.
  • This surface expression creates a cancer-specific antigen amenable to antibody and cellular immunotherapies.
INSIGHT

Antibodies Show Early Molecular Responses

  • Early antibody trials show rapid, large molecular reductions in mutant CALR allele burden on treatment.
  • Targeting the malignant clone directly could change disease natural history beyond symptomatic JAK inhibition.
ADVICE

Expand Dosing And Follow Patients Long-Term

  • Continue dose escalation and expand cohorts to define optimal dosing and efficacy for INCA33989.
  • Follow patients long-term to confirm durability and translate biomarker signals into clinical pathways.
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