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

(2017) ONCOIMMUNOLOGY. 7(3).
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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

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Chicago
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).
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).
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).
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.
@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, Genevi{\`e}ve and Bultinck, Jennyfer and Paul, Franciane and Gerlo, Sarah and Van Der Heyden, Jos{\'e} and Bordat, Yann and Catteeuw, Dominiek and De Cauwer, Lode and Rogge, Elke and Verhee, Annick and Uz{\'e}, Gilles and Tavernier, Jan},
  issn         = {2162-402X},
  journal      = {ONCOIMMUNOLOGY},
  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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