Mutant Calreticulin (CALR) drives myeloproliferative neoplasms, targeted by peptide vaccines and antibodies.

Myeloproliferative neoplasms (MPNs) are chronic myeloid blood cancers. A significant subset, BCR:ABL1-negative classical MPNs, are driven by mutations in the calreticulin (CALR) gene. Current treatments often focus on symptom control, leaving a critical gap for disease-modifying therapies that specifically target the underlying clonal driver. Mutant CALR constitutively activates the thrombopoietin receptor and generates tumor-specific neoepitopes, making it an attractive target for selective immunotherapy.

This comprehensive review synthesizes preclinical and clinical evidence on therapeutic strategies targeting mutant calreticulin (CALR) in myeloproliferative neoplasms (MPNs). It meticulously summarized wild-type CALR functions and the molecular consequences of mutant CALR, including altered subcellular localization and receptor activation. The review specifically examined various immunotherapeutic approaches, such as peptide-based vaccines, monoclonal antibodies, T-cell engagers, and chimeric antigen receptor T-cell therapies, with a particular focus on the clinically evaluated mutant CALR-targeting monoclonal antibody, INCA033989.