Development of a high-affinity anti-ROR1 variable region for broad anti-cancer immunotherapy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed in aggressive triple-negative breast cancer (TNBC).
• Current ROR1-targeting therapies, like CAR T cells, show promise but face challenges with efficacy and toxicity.
• Natural Killer (NK) cell-based immunotherapies offer a potentially safer alternative for cancer treatment.

Purpose of the Study:

• To develop novel ROR1-targeting immunotherapies for TNBC.
• To evaluate the efficacy of ROR1-targeting chimeric monoclonal antibodies and CAR NK cells against TNBC.
• To investigate the synergistic effect of TGF-β inhibition on ROR1-targeting therapies.

Main Methods:

• Development of a phage-derived single-chain fragment variable (scFv) targeting ROR1.
• Generation of scFv-derived chimeric monoclonal antibodies and ROR1-specific CAR NK cells.
• Assessment of anti-cancer efficacy against TNBC cells and evaluation of TGF-β inhibition strategies.

Main Results:

• The developed scFv-based antibodies and CAR NK cells demonstrated anti-cancer efficacy against TNBC cells.
• ROR1-targeting therapies showed improved persistence and efficacy when combined with TGF-β inhibition.
• TGF-β inhibition was achieved using small-molecule inhibitors or CRISPR-Cas9-edited NK cells.

Conclusions:

• Novel ROR1-targeting immunotherapies, including CAR NK cells, are effective against TNBC.
• Combining ROR1-targeting strategies with TGF-β inhibition significantly enhances therapeutic outcomes.
• These findings support the development of advanced ROR1-based immunotherapies for TNBC treatment.