Engineering Axl specific CAR and SynNotch receptor for cancer therapy

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Axl, a tyrosine kinase receptor, is frequently overexpressed in various cancers, making it a significant therapeutic target.
• Chimeric antigen receptor (CAR) T cell therapy has shown high efficacy in treating cancers, particularly B cell malignancies.
• Synthetic Notch (synNotch) receptors offer enhanced specificity and payload delivery for CAR T cell therapy in an antigen-dependent manner.

Purpose of the Study:

• To develop novel CAR and synNotch receptors targeting the cancer-associated receptor Axl.
• To evaluate the therapeutic potential of anti-Axl CAR and synNotch receptors in T cell-based cancer therapies.

Main Methods:

• Generation of a single-chain variable fragment (scFv) from a humanized monoclonal antibody targeting Axl.
• Construction of an anti-Axl CAR by linking the scFv to CD3ζ, CD28, and 4-1BB signaling domains.
• Development of an anti-Axl synNotch receptor utilizing the same Axl-targeting scFv.

Main Results:

• The anti-Axl CAR, when introduced into human primary T cells, induced cytokine production and tumor cell killing in response to Axl-expressing cancer cells.
• The anti-Axl synNotch receptor demonstrated activation upon encountering Axl-expressing tumor cells.
• Both developed receptors showed antigen-dependent activity against Axl-positive targets.

Conclusions:

• Engineered anti-Axl CAR and synNotch receptors are valuable reagents for developing targeted cancer therapies.
• These receptors hold promise for treating a range of cancers where Axl is overexpressed.
• The study validates Axl as a viable target for novel immunotherapeutic strategies.