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

(2017) ONCOIMMUNOLOGY. 7(3).
Author
Organization
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, checkpoint inhibitors, dendritic cells, engineered immunocytokine, Immunotherapy, targeting, toxicity, type I interferon, tumor microenvironment, CD8-ALPHA(+) DENDRITIC CELLS, IMMUNE CHECKPOINT BLOCKADE, CANCER-THERAPY, PD-1 BLOCKADE, IMMUNOGENIC TUMORS, BACTERIAL-DNA, CLINICAL USE, ACTIVATION, MOUSE, TOXICITIES

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Citation

Please use this url to cite or link to this publication:

MLA
Cauwels, Anje et al. “A Safe and Highly Efficient Tumor-targeted Type I Interferon Immunotherapy Depends on the Tumor Microenvironment.” ONCOIMMUNOLOGY 7.3 (2017): n. pag. Print.
APA
Cauwels, A., Van Lint, S., Garcin, G., Bultinck, J., Paul, F., Gerlo, S., Van Der Heyden, J., et al. (2017). A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment. ONCOIMMUNOLOGY, 7(3).
Chicago author-date
Cauwels, Anje, Sandra Van Lint, Geneviève Garcin, Jennyfer Bultinck, Franciane Paul, Sarah Gerlo, José Van Der Heyden, et al. 2017. “A Safe and Highly Efficient Tumor-targeted Type I Interferon Immunotherapy Depends on the Tumor Microenvironment.” Oncoimmunology 7 (3).
Chicago author-date (all authors)
Cauwels, Anje, Sandra Van Lint, Geneviève Garcin, Jennyfer Bultinck, Franciane Paul, Sarah Gerlo, José Van Der Heyden, Yann Bordat, Dominiek Catteeuw, Lode De Cauwer, Elke Rogge, Annick Verhee, Gilles Uzé, and Jan Tavernier. 2017. “A Safe and Highly Efficient Tumor-targeted Type I Interferon Immunotherapy Depends on the Tumor Microenvironment.” Oncoimmunology 7 (3).
Vancouver
1.
Cauwels A, Van Lint S, Garcin G, Bultinck J, Paul F, Gerlo S, et al. A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment. ONCOIMMUNOLOGY. 2017;7(3).
IEEE
[1]
A. Cauwels et al., “A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment,” ONCOIMMUNOLOGY, vol. 7, no. 3, 2017.
@article{8550250,
  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.},
  articleno    = {e1398876},
  author       = {Cauwels, Anje and Van Lint, Sandra and Garcin, Geneviève and Bultinck, Jennyfer and Paul, Franciane and Gerlo, Sarah and Van Der Heyden, José and Bordat, Yann and Catteeuw, Dominiek and De Cauwer, Lode and Rogge, Elke and Verhee, Annick and Uzé, Gilles and Tavernier, Jan},
  issn         = {2162-402X},
  journal      = {ONCOIMMUNOLOGY},
  keywords     = {AcTaferon,checkpoint inhibitors,dendritic cells,engineered immunocytokine,Immunotherapy,targeting,toxicity,type I interferon,tumor microenvironment,CD8-ALPHA(+) DENDRITIC CELLS,IMMUNE CHECKPOINT BLOCKADE,CANCER-THERAPY,PD-1 BLOCKADE,IMMUNOGENIC TUMORS,BACTERIAL-DNA,CLINICAL USE,ACTIVATION,MOUSE,TOXICITIES},
  language     = {eng},
  number       = {3},
  pages        = {13},
  title        = {A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment},
  url          = {http://dx.doi.org/10.1080/2162402x.2017.1398876},
  volume       = {7},
  year         = {2017},
}

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