Masked Chimeric Antigen Receptor for Tumor-Specific Activation

• Published in: Molecular therapy Vol. 25; no. 1; pp. 274 - 284
• Main Authors: Han, Xiaolu, Bryson, Paul D., Zhao, Yifan, Cinay, Gunce E., Li, Si, Guo, Yunfei, Siriwon, Natnaree, Wang, Pin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.01.2017; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: Animals; Antigen (tumor-associated); Antigens; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Antitumor activity; Binding sites; Cancer; Cancer immunotherapy; Cell Line, Tumor; Chimeric antigen receptors; Clinical trials; Cytokines - metabolism; Cytotoxicity; Disease Models, Animal; Epidermal growth factor; Epidermal growth factor receptors; Feasibility studies; Female; Gene Order; Genetic Vectors - genetics; Humans; Immunotherapy; Immunotherapy, Adoptive; Lymphocyte Activation - immunology; Lymphocyte Subsets - immunology; Lymphocyte Subsets - metabolism; Lymphocytes; Lymphocytes T; Mice; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Original; Peptides; Protein Binding - immunology; Proteolysis; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Statistical analysis; T cell receptors; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2016.10.011

Adoptive cellular therapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) cells is a powerful form of cancer immunotherapy. CAR-T cells can be redirected to specifically recognize tumor-associated antigens (TAAs) and induce high levels of antitumor activity. However, they may also display “on-target off-tumor” toxicities, resulting from low-level expression of TAAs in healthy tissues. These adverse effects have raised considerable safety concerns and limited the clinical application of this otherwise promising therapeutic modality. To minimize such side effects, we have designed an epidermal growth factor receptor (EGFR)-specific masked CAR (mCAR), which consists of a masking peptide that blocks the antigen-binding site and a protease-sensitive linker. Proteases commonly active in the tumor microenvironment can cleave the linker and disengage the masking peptide, thereby enabling CAR-T cells to recognize target antigens only at the tumor site. In vitro mCAR showed dramatically reduced antigen binding and antigen-specific activation in the absence of proteases, but normal levels of binding and activity upon treatment with certain proteases. Masked CAR-T cells also showed antitumor efficacy in vivo comparable to that of unmasked CAR. Our study demonstrates the feasibility of improving the safety profile of conventional CARs and may also inspire future design of CAR molecules targeting broadly expressed TAAs. [Display omitted] Wang and colleagues report a novel design of masked CAR to address one of the most crucial limitations of CAR-T cell therapy, on-target off-tumor toxicity. This adds to the existing efforts of extending the application of CAR-T cell therapy beyond CD19-positive malignancies and specifically to solid tumors.