Acquired and Selected: Tracking Antigen Escape during T Cell-Redirecting Therapies in Multiple Myeloma

Area of Science:

• Oncology
• Genomics
• Immunotherapy

Background:

• BCMA- and GPRC5D-directed immunotherapies show promise for blood cancers.
• Genomic antigen escape is a potential mechanism of treatment resistance.
• Monitoring antigen escape requires robust methodologies.

Purpose of the Study:

• To develop and implement a temporal workflow for monitoring genomic antigen escape.
• To investigate the origin of mutations associated with antigen escape during immunotherapy.

Main Methods:

• Utilized a temporal workflow to track genomic alterations.
• Employed chemotherapy-induced mutational signatures as molecular barcodes.
• Analyzed genomic data from patients undergoing BCMA- or GPRC5D-directed immunotherapy.

Main Results:

• Demonstrated the acquisition of mutations during immunotherapy.
• Provided evidence that these mutations arise during therapy.
• Distinguished therapy-acquired mutations from pre-existing ones.

Conclusions:

• Chemotherapy-induced mutational signatures serve as effective barcodes for tracking antigen escape.
• Genomic mutations conferring antigen escape are acquired during BCMA- or GPRC5D-directed immunotherapy.
• This temporal monitoring approach aids in understanding resistance mechanisms in blood cancer treatment.