期刊
ONCOIMMUNOLOGY
卷 7, 期 3, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2017.1398876
关键词
AcTaferon; checkpoint inhibitors; dendritic cells; engineered immunocytokine; Immunotherapy; targeting; toxicity; type I interferon; tumor microenvironment
资金
- UGent Methusalem grant
- Advanced ERC (CYRE) grant [340941]
- FWO-V grant [G009614 N]
- LabEx MabImprove
- Institut Carnot CALYM
- Canceropole - Institut National du Cancer (INCa)
- SIRIC Montpellier Cancer INCa-DGOS-Inserm [6045]
- Orionis Biosciences
Despite approval for the treatment of various malignancies, clinical application of cytokines such as type I interferon (IFN) is severely impeded by their systemic toxicity. AcTakines (Activity-on-Target cytokines) are optimized immunocytokines that, when injected in mice, only reveal their activity upon cell-specific impact. We here show that type I IFN-derived AcTaferon targeted to the tumor displays strong antitumor activity without any associated toxicity, in contrast with wild type IFN. Treatment with CD20-targeted AcTaferon of CD20(+) lymphoma tumors or melanoma tumors engineered to be CD20(+), drastically reduced tumor growth. This antitumor effect was completely lost in IFNAR- or Batf3-deficient mice, and depended on IFN signaling in conventional dendritic cells. Also the presence of, but not the IFN signaling in, CD8(+) T lymphocytes was critical for proficient antitumor effects. When combined with immunogenic chemotherapy, low-dose TNF, or immune checkpoint blockade strategies such as anti-PDL1, anti-CTLA4 or anti-LAG3, complete tumor regressions and subsequent immunity (memory) were observed, still without any concomitant morbidity, again in sharp contrast with wild type IFN. Interestingly, the combination therapy of tumor-targeted AcTaferon with checkpoint inhibiting antibodies indicated its ability to convert nonresponding tumors into responders. Collectively, our findings demonstrate that AcTaferon targeted to tumor-specific surface markers may provide a safe and generic addition to cancer (immuno)therapies.
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