Citation

  • Authors: Cauwels, A., Van Lint, S., Garcin, G., Bultinck, J., Paul, F., Gerlo, S., Van der Heyden, J., Bordat, Y., Catteeuw, D., De Cauwer, L., Rogge, E., Verhee, A., Uze, G., Tavernier, J.
  • Year: 2018
  • Journal: Oncoimmunology 7 e1398876
  • Applications: in vitro / DNA / jetPRIME
  • Cell type: B16-BL6
    Description: Murine melanoma
    Known as: B16/BL6 ; B16 BL6 ; B16BL6 ; B16BL-6 ; BL6 ; BL-6 ; B16-F10-BL6

Method

CRISPR KO

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.

Pubmed