Developing ROR1 Targeting CAR-T Cells against Solid Tumors in Preclinical Studies.

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• CAR-T therapy shows success in B-cell malignancies but faces challenges in solid tumors due to target scarcity.
• Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a promising target due to its aberrant expression on various tumors and low expression on healthy tissues.

Purpose of the Study:

• To develop and evaluate ROR1-targeted CAR-T cells for solid tumor treatment.
• To compare the efficacy and functionality of two ROR1 CAR constructs with different hinge regions.

Main Methods:

• Construction of two ROR1 CARs using the Zilovertamab recognition domain with varying hinge regions (short IgG4 vs. long).
• In vitro assessment of CAR surface expression and functionality.
• In vivo evaluation of ROR1 CAR-T efficacy and toxicity in three human solid tumor xenograft mouse models.

Main Results:

• Both ROR1 CAR constructs specifically targeted ROR1+ cancer cells.
• The CAR with a shorter IgG4 hinge demonstrated superior surface expression and in vitro functionality.
• ROR1 CAR-T therapy effectively controlled solid tumor growth in vivo across three models without significant toxicity.

Conclusions:

• ROR1 CAR-T cells, particularly those derived from Zilovertamab with a shorter hinge, are efficacious and safe for suppressing ROR1+ solid tumors.
• This approach presents a promising therapeutic strategy for ROR1-expressing solid tumors, warranting further clinical investigation.