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Developing ROR1 Targeting CAR-T Cells against Solid Tumors in Preclinical Studies
Boon Kiat Lee1, Yuhua Wan2, Zan Lynn Chin1
1SPH Biotherapeutics (HK) Limited, Unit G01/02, Building 15W, Science Park Phase III, Hong Kong Science and Technology Park, NT, Hong Kong.
Abstract:
Chimeric antigen receptor (CAR)-modified T-cells (CAR-T) have demonstrated promising clinical benefits against B-cell malignancies. Yet, its application for solid tumors is still facing challenges. Unlike haematological cancers, solid tumors often lack good targets, which are ideally expressed on the tumor cells, but not by the normal healthy cells. Fortunately, receptor tyrosine kinase-like orphan receptor 1 (ROR1) is among a few good cancer targets that is aberrantly expressed on various tumors but has a low expression on normal tissue, suggesting it as a good candidate for CAR-T therapy. Here, we constructed two ROR1 CARs with the same antigen recognition domain that was derived from Zilovertamab but differing in hinge regions. Both CARs target ROR1+ cancer cells specifically, but CAR with a shorter IgG4 hinge exhibits a higher surface expression and better in vitro functionality. We further tested the ROR1 CAR-T in three human solid tumor xenografted mouse models. Our ROR1 CAR-T cells controlled the solid tumor growth without causing any severe toxicity. Our results demonstrated that ROR1 CAR-T derived from Zilovertamab is efficacious and safe to suppress ROR1+ solid tumors in vitro and in vivo, providing a promising therapeutic option for future clinical application.
Insights
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) CAR-T cells show promise for solid tumors. ROR1 CAR-T therapy effectively suppressed ROR1+ solid tumors in preclinical models with good safety.
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.
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