A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment

Oncoimmunology. 2017 Nov 27;7(3):e1398876. doi: 10.1080/2162402X.2017.1398876. eCollection 2018.

Abstract

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.

Keywords: AcTaferon; Immunotherapy; checkpoint inhibitors; dendritic cells; engineered immunocytokine; targeting; toxicity; tumor microenvironment; type I interferon.

Publication types

  • Research Support, Non-U.S. Gov't

Grant support

This work was supported by UGent Methusalem and Advanced ERC (CYRE, N° 340941) grants to J.T.; an FWO-V grant G009614 N to J.T. and S.G.; grants from LabEx MabImprove, Institut Carnot CALYM, the Canceropôle – Institut National du Cancer (INCa) to G.U.; the SIRIC Montpellier Cancer INCa-DGOS-Inserm 6045 to F.P.; and by Orionis Biosciences .