ROR1-targeting switchable CAR-T cells for cancer therapy

Area of Science:

• Immunotherapy
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor T cell (CAR-T) therapy is successful in hematologic malignancies.
• Switchable CAR-T (sCAR-T) systems offer enhanced control and versatility.
• Receptor tyrosine kinase ROR1 is a target expressed in various cancers.

Purpose of the Study:

• To evaluate sCAR-T therapy targeting ROR1 for cancer treatment.
• To identify effective bispecific adapter proteins for universal CAR-T engagement.
• To compare the efficacy of different ROR1-targeting CAR-T strategies.

Main Methods:

• Developed and compared a panel of ROR1-targeting sCAR-T systems with varying Fab affinities and epitopes.
• Utilized in vitro and in vivo models of ROR1-expressing cancers.
• Assessed antitumor activity and CAR-T engagement mediated by different bispecific adapters.

Main Results:

• Switch potency correlated with affinity for antibodies targeting identical or overlapping epitopes.
• A low-affinity switch targeting a unique epitope exhibited potent and selective in vitro and in vivo anti-tumor activity.
• The anti-ROR1 antibody (324) used in the sCAR-T system outperformed a conventional CAR-T based on a higher-affinity antibody (R12).

Conclusions:

• sCAR-T therapy targeting ROR1 demonstrates significant therapeutic potential.
• sCAR-T systems facilitate efficient screening for novel CAR-T candidates.
• This approach can accelerate the identification of promising CAR-T therapies for clinical development.