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Splicing-Mediated Antigen Escape from Immunotherapy for B-cell Malignancies
Jessie Bourcier1, Omar Abdel-Wahab1
1Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Blood Cancer Discovery
|January 11, 2022
Summary
Alternative RNA splicing of CD22 in B-cell acute lymphoblastic leukemia can lead to immune escape from CD22-targeted therapies. Pre-existing drug-resistant CD22 forms in leukemia cells impact treatment response to immunotherapies.
Area of Science:
- Immunology
- Hematology
- Oncology
Background:
- B-cell acute lymphoblastic leukemia (B-ALL) is a significant hematologic malignancy.
- CD22-targeted immunotherapies have shown promise in treating B-ALL.
- Mechanisms of therapeutic resistance in B-ALL require further elucidation.
Discussion:
- Alternative RNA splicing of the CD22 gene in B-ALL cells generates drug-resistant isoforms.
- These isoforms can mediate antigen escape, reducing the efficacy of CD22-targeted treatments.
- Leukemic cells may harbor these resistant isoforms prior to treatment initiation.
Key Insights:
- Identified alternative RNA splicing of CD22 as a mechanism for immune escape in B-ALL.
- Demonstrated that pre-existing CD22 isoforms influence response to CD22-directed therapies.
- Highlighted the impact on antibody-drug conjugates (e.g., inotuzumab ozogamicin) and immunotoxins (e.g., moxetumomab pasudotox).
- Showed implications for anti-CD22 chimeric antigen receptor T-cell therapy.
Outlook:
- Further research into CD22 splicing variants may reveal new therapeutic targets.
- Strategies to overcome resistance mediated by CD22 isoforms are needed.
- Personalized treatment approaches considering CD22 expression profiles could improve outcomes.
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