PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies

作者：Yamin Jie, Guijun Liu, Lina Feng, Ying Li, E Mingyan, Liangliang Wu, Yinyin Li, Guanghua Rong, Yongwu Li, Huafeng Wei, Anxin Gu · 发表于：Frontiers in Immunology · 年份：2021 · DOI：10.3389/fimmu.2021.665970 · 被引用次数：58 · 研究领域：CAR-T cell therapy research、Virus-based gene therapy research、Viral Infectious Diseases and Gene Expression in Insects

In spite of impressive success in treating hematologic malignancies, adoptive therapy with chimeric antigen receptor modified T cells (CAR T) has not yet been effective in solid tumors, where identification of suitable tumor-specific antigens remains a major obstacle for CAR T-cell therapy due to the “on target off tumor” toxicity. Protein tyrosine kinase 7 (PTK7) is a member of the Wnt-related pseudokinases and identified as a highly expressed antigen enriched in cancer stem cells (CSCs) from multiple solid tumors, including but not limited to triple-negative breast cancer, non-small-cell lung cancer, and ovarian cancer, suggesting it may serve as a promising tumor-specific target for CAR T-cell therapy. In this study, we constructed three different PTK7-specific CAR (PTK7-CAR1/2/3), each comprising a humanized PTK7-specific single-chain variable fragment (scFv), hinge and transmembrane (TM) regions of the human CD8α molecule, 4-1BB intracellular co-stimulatory domain (BB-ICD), and CD3ζ intracellular domain (CD3ζ-ICD) sequence, and then prepared the CAR T cells by lentivirus-mediated transduction of human activated T cells accordingly, and we sequentially evaluated their antigen-specific recognition and killing activity in vitro and in vivo . T cells transduced with all three PTK7-CAR candidates exhibited antigen-specific cytokine production and potent cytotoxicity against naturally expressing PTK7-positive tumor cells of multiple cancer types without mediating cytotoxicity ...