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Background
Chimeric antigen receptor (CAR)-NK cells are a promising and safe alternative to CAR-T cells. However, the limited persistence in vivo restricts their clinical application and sustained therapeutic responses. IL-15 has been extensively used to improve CAR-NK cell persistence and effectiveness. Nevertheless, accumulation of IL-15 might induce uncontrolled proliferation of CAR-NK cells and thus lead to fatal side-effects. Therefore, it is essential to develop a safe and effective alternative strategy to improve the persistence and anti-tumor activity of CAR-NK cells.
Methods
A signaling intact membrane-bound IL-15 (mbIL-15) was designed by fusing IL-15 and full-length IL-15Rα and was systematically compared with secretory IL-15 (sIL-15) in a B7H3-targeting CAR-NK cell system regarding their functionality and safety through various in vitro and in vivo experiments.
Results
Both expression of sIL-15 or mbIL-15 significantly enhanced the proliferation by activating STAT5 and improved anti-tumor activity of CAR-NK cells in vitro and in vivo . Although CAR-NK cells with sIL-15 quickly eliminated intraperitoneal ovarian cancer, the mice experienced severe consequences, including dysregulated CAR-NK cell expansion, intense inflammatory responses, and irreversible organ damages. In contrast, CAR-NK cells carrying mbIL-15 showed moderate cell proliferation and potent tumor killing activity without observable adverse effects in both local treatment and systemic administration models.
Conclusion
Head-to-head comparative studies demonstrated that signaling intact mbIL-15 significantly improved therapeutic efficacy and safety of CAR-NK cells compared to sIL-15, which provided preclinical evidence for future clinical development.
Details
Antibodies;
Cytotoxicity;
Lymphocytes T;
Cloning;
Cytokines;
Cell proliferation;
Natural killer cells;
Clinical trials;
Tumors;
Flow cytometry;
Stat5 protein;
Antigens;
Peptides;
Penicillin;
Vectors (Biology);
Chimeric antigen receptors;
Antitumor agents;
Cell culture;
Interleukin 15;
Product development
1 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
2 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China, Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu, China
3 The Second Clinical Medical School, Nanjing Medical University, Nanjing, Jiangsu, China
4 Department of Obstetrics and Gynecology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
5 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China, Department of Obstetrics and Gynecology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
6 Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu, China