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Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
Published on: March 10, 2023
From JAK to CALR: redefining therapeutic targets in myeloproliferative neoplasms
Anushri Soni1, Amit Verma2, Swati Goel2
1Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Abstract:
This review highlights the emergence of CALR as a promising therapeutic target in CALR-mutated myeloproliferative neoplasms. While current JAK inhibitors alleviate symptoms and reduce thrombosis risk, they lack clonal specificity, have a limited impact on the natural history of disease, and are limited by toxicity and resistance. In contrast, CALR mutations generate a unique, disease-specific neoepitope that drives disease pathogenesis through aberrant MPL activation and is accessible on the cell surface, making it an ideal immunologic and antibody target. Preclinical and early clinical advances - including monoclonal antibodies, bispecific T-cell engagers, CAR-T therapies, antibody-drug conjugates, and peptide/viral vector vaccines - have demonstrated selective activity against CALR-mutant clones while sparing normal hematopoiesis, with encouraging evidence of molecular remissions and disease modification. Although challenges such as immune tolerance remain, mutant CALR-directed therapies represent a potential transformative shift in essential thrombocythemia, and primary myelofibrosis treatment.
Insights
Calreticulin (CALR) mutations offer a novel therapeutic target for myeloproliferative neoplasms. Therapies targeting these CALR mutations show promise for disease modification and molecular remission.
Area of Science:
- Hematology
- Oncology
- Immunotherapy
Background:
- Myeloproliferative neoplasms (MPNs) are driven by various mutations, including those in CALR.
- Current treatments like JAK inhibitors have limitations in specificity and disease modification.
- CALR mutations create a unique neoepitope, making it a targetable antigen.
Purpose of the Study:
- To review the therapeutic potential of targeting CALR mutations in MPNs.
- To explore novel immunotherapeutic strategies against CALR-mutated clones.
Main Methods:
- Review of preclinical and early clinical data on CALR-directed therapies.
- Analysis of various immunotherapeutic approaches including antibodies, CAR-T, and vaccines.
Main Results:
- CALR-directed therapies demonstrate selective activity against CALR-mutant clones.
- Encouraging evidence of molecular remissions and disease modification observed.
- These therapies spare normal hematopoiesis, reducing off-target effects.
Conclusions:
- Targeting CALR mutations represents a promising therapeutic strategy for MPNs.
- Novel immunotherapies offer a potential paradigm shift in treating essential thrombocythemia and primary myelofibrosis.
- Further research is needed to overcome challenges like immune tolerance.
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