Engineering Axl specific CAR and SynNotch receptor for cancer therapy

• Published in: Scientific reports 2018-03, Vol.8 (1), p.3846-3846, Article 3846
• Main Authors: Cho, Jang Hwan, Okuma, Atsushi, Al-Rubaye, Dalal, Intisar, Ejaj, Junghans, Richard P., Wong, Wilson W.
• Format: Article
• Language: English
• Subjects: 13; 13/21; 13/31; 631/250/251; 631/553/552; Antibodies, Monoclonal, Humanized; Antigens; Axl protein; Axl Receptor Tyrosine Kinase; Cancer; Cancer therapies; CD28 antigen; Cell Line, Tumor; Chimeric antigen receptors; Clinical trials; Humanities and Social Sciences; Humans; Immunotherapy, Adoptive; Jurkat Cells; K562 Cells; Lymphocytes B; Lymphocytes T; Monoclonal antibodies; multidisciplinary; Protein Engineering - methods; Protein-tyrosine kinase receptors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Reagents; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Antigen, T-Cell - immunology; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - metabolism; Receptors, Notch - genetics; Receptors, Notch - metabolism; Science; Science (multidisciplinary); Signal Transduction; Single-Chain Antibodies - immunology; T-Lymphocytes - immunology; Therapeutic applications; Tumor cells; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-22252-6

Axl is a tyrosine kinase receptor that is commonly overexpressed in many cancers. As such, Axl represents an attractive therapeutic target. The transfer of engineered T cell expressing chimeric antigen receptor (CAR) is an exciting cancer therapeutic approach that shows high efficacy against cancers in clinical trials, especially for B cell malignancies. Furthermore, recently developed synthetic Notch (synNotch) receptor has demonstrated potential in enhancing the specificity of CAR T cell therapy and delivering therapeutic payloads to tumors in an antigen-dependent manner. Therefore, a CAR or synNotch against Axl could be a valuable therapeutic reagent against many cancers. Here, we develop a single-chain variable fragment from a humanized monoclonal antibody against Axl. The scFv is attached to CD3ζ, CD28, and 4-1BB signaling domains to generate an anti-Axl CAR. When introduced into human primary T cells, the anti-Axl CAR can lead to cytokine production and cell killing in response to tumor cells expressing Axl. Moreover, an anti-Axl synNotch generated using the same scFv can be activated with Axl expressing tumor cells. Given the fact that Axl is an important cancer therapeutic target, these receptors could be valuable reagents for developing anti-Axl therapies.