癌症研究
溶瘤病毒
免疫系统
免疫疗法
免疫学
癌细胞
癌症免疫疗法
癌症
生物
医学
遗传学
作者
Kok‐Siong Chen,Clemens Reinshagen,Thijs van Schaik,Filippo Rossignoli,Paulo Borges,Natalia Claire Mendonca,Reza Abdi,Brennan Simon,David A. Reardon,Hiroaki Wakimoto,Khalid Shah
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2023-01-04
卷期号:15 (677)
被引量:15
标识
DOI:10.1126/scitranslmed.abo4778
摘要
The administration of inactivated tumor cells is known to induce a potent antitumor immune response; however, the efficacy of such an approach is limited by its inability to kill tumor cells before inducing the immune responses. Unlike inactivated tumor cells, living tumor cells have the ability to track and target tumors. Here, we developed a bifunctional whole cancer cell-based therapeutic with direct tumor killing and immunostimulatory roles. We repurposed the tumor cells from interferon-β (IFN-β) sensitive to resistant using CRISPR-Cas9 by knocking out the IFN-β-specific receptor and subsequently engineered them to release immunomodulatory agents IFN-β and granulocyte-macrophage colony-stimulating factor. These engineered therapeutic tumor cells (ThTCs) eliminated established glioblastoma tumors in mice by inducing caspase-mediated cancer cell apoptosis, down-regulating cancer-associated fibroblast-expressed platelet-derived growth factor receptor β, and activating antitumor immune cell trafficking and antigen-specific T cell activation signaling. This mechanism-based efficacy of ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The incorporation of a double kill-switch comprising herpes simplex virus-1 thymidine kinase and rapamycin-activated caspase 9 in ThTCs ensured the safety of our approach. Arming naturally neoantigen-rich tumor cells with bifunctional therapeutics represents a promising cell-based immunotherapy for solid tumors and establishes a road map toward clinical translation.
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