期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-20599-x
关键词
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资金
- EU [602239]
- Swiss National Science Foundation [733 310030_170320, 310030_188450, CRSII5_183478]
- European Union [826121]
- Cancer Research UK Biotherapeutics Drug Discovery Project Award [C22442/A20766]
- Wellcome Trust Clinician Scientist Fellowship
- Great Ormond Street Hospital Children's Charity Clinical Starter Grant [V1287]
- University College London Hospital Biomedical Research Centre
- Cancer Research U.K. (CRUK) Senior Cancer Research Fellowship [C36463/A22246]
- CRUK Biotherapeutic Program Grant [C36463/A20764]
- University Research Priority Program (URPP) postdoctoral fellowship
- SARRP system
- EPSRC [EP/L006472/1] Funding Source: UKRI
Research shows that local delivery of IL-12 combined with CAR-T cell therapy can achieve durable anti-tumor responses by enhancing cytotoxicity of CAR-T cells, reshaping the tumor microenvironment, promoting immune cell infiltration, and activating the myeloid compartment.
Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4(+) T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM.
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