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TEACHING AN OLD DOG NEW TRICKS: ACTIVITY-ON-TARGET INTERFERON TO TREAT T-ALL

Steven Goossens (UGent) , Anje Cauwels (UGent) , Tim Pieters (UGent) , Willem Daneels (UGent) , Pieter Van Vlierberghe (UGent) and Jan Tavernier (UGent)
Author
Organization
Abstract
Background Type 1 interferon (IFN) has a long history in the treatment of cancer, including hematological malignancies. The anti-cancer effects induced by IFN result from a combination of 1) direct cancer cell growth inhibition by cell cycle arrest, apoptosis, or differentiation and 2) the activation of the immune system involving antigen presentation by Clec9A+ dendritic cells and priming of cytotoxic CD8+ T-cells. However, IFN therapy experienced variable and unpredictable success in the clinic. Its clinical application is severely impeded by a complex pattern of adverse side-effects, due to the multifaceted activity pattern of IFN. Therefore, safe exploitation of the anti-cancer potential of IFN requires strategies to direct their activity to selected target cells, avoiding systemic toxicity. Aims Safe exploitation of the anti-cancer potential of IFN requires strategies to direct their activity to selected target cells, avoiding systemic toxicity. Methods To improve the therapeutic index of IFN, we have developed AcTaferons (Activity-on-Target Interferon), optimized (mutant) immunocytokines. Mutated IFNa2Q124R, with a strongly reduced affinity for its receptor complex, was fused to single domain antibodies targeting cell-specific domains, which selectively restores the AcTaferon (AFN) activity in a cell-type specific manner. As such, CD8-AFN and Clec9A-AFN were generated which selectively target either CD8+ T(-ALL) cells or Clec9A+ dendritic cells. Results Using CD8- and CD8+ mouse T-ALL cell lines, we evaluated the direct and indirect anti-leukemic effects of our novel AFNs, in vitro and in vivo upon transplantation in immunocompromised and immunocompetent syngeneic hosts. A significant reduction in the leukemic burden was observed. These anti-cancer effects of AFN were similar as observed for the wildtype IFN, but in a cell-type specific manner and with drastically reduced adverse side-effects. Monotherapy was even sufficient to completely cure a proportion of leukemic mice, which highlights the strong anti-leukemic power of these optimized immunocytokines. Strinkingly only the direct effect CD8-AFN on in vivo CD8+ T-ALL was synergistic with asparaginase treatment. No synergism was observed between asparaginase and the indirect immune-mediated Clec9A-AFN anti-leukemic effect. Conclusion In conclusion, we have developed novel optimized immunocytokines as an off-the-shelve targeted immunotherapy for T-ALL.

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MLA
Goossens, Steven, et al. “TEACHING AN OLD DOG NEW TRICKS: ACTIVITY-ON-TARGET INTERFERON TO TREAT T-ALL.” EHA Library, European Hematology Association, 2020.
APA
Goossens, S., Cauwels, A., Pieters, T., Daneels, W., Van Vlierberghe, P., & Tavernier, J. (2020). TEACHING AN OLD DOG NEW TRICKS: ACTIVITY-ON-TARGET INTERFERON TO TREAT T-ALL. In EHA Library. European Hematology Association.
Chicago author-date
Goossens, Steven, Anje Cauwels, Tim Pieters, Willem Daneels, Pieter Van Vlierberghe, and Jan Tavernier. 2020. “TEACHING AN OLD DOG NEW TRICKS: ACTIVITY-ON-TARGET INTERFERON TO TREAT T-ALL.” In EHA Library. European Hematology Association.
Chicago author-date (all authors)
Goossens, Steven, Anje Cauwels, Tim Pieters, Willem Daneels, Pieter Van Vlierberghe, and Jan Tavernier. 2020. “TEACHING AN OLD DOG NEW TRICKS: ACTIVITY-ON-TARGET INTERFERON TO TREAT T-ALL.” In EHA Library. European Hematology Association.
Vancouver
1.
Goossens S, Cauwels A, Pieters T, Daneels W, Van Vlierberghe P, Tavernier J. TEACHING AN OLD DOG NEW TRICKS: ACTIVITY-ON-TARGET INTERFERON TO TREAT T-ALL. In: EHA Library. European Hematology Association; 2020.
IEEE
[1]
S. Goossens, A. Cauwels, T. Pieters, W. Daneels, P. Van Vlierberghe, and J. Tavernier, “TEACHING AN OLD DOG NEW TRICKS: ACTIVITY-ON-TARGET INTERFERON TO TREAT T-ALL,” in EHA Library, 2020.
@inproceedings{8667342,
  abstract     = {Background
Type 1 interferon (IFN) has a long history in the treatment of cancer, including hematological malignancies. The anti-cancer effects induced by IFN result from a combination of 1) direct cancer cell growth inhibition by cell cycle arrest, apoptosis, or differentiation and 2) the activation of the immune system involving antigen presentation by Clec9A+ dendritic cells and priming of cytotoxic CD8+ T-cells. However, IFN therapy experienced variable and unpredictable success in the clinic. Its clinical application is severely impeded by a complex pattern of adverse side-effects, due to the multifaceted activity pattern of IFN. Therefore, safe exploitation of the anti-cancer potential of IFN requires strategies to direct their activity to selected target cells, avoiding systemic toxicity.
Aims
Safe exploitation of the anti-cancer potential of IFN requires strategies to direct their activity to selected target cells, avoiding systemic toxicity.
Methods
To improve the therapeutic index of IFN, we have developed AcTaferons (Activity-on-Target Interferon), optimized (mutant) immunocytokines. Mutated IFNa2Q124R, with a strongly reduced affinity for its receptor complex, was fused to single domain antibodies targeting cell-specific domains, which selectively restores the AcTaferon (AFN) activity in a cell-type specific manner. As such, CD8-AFN and Clec9A-AFN were generated which selectively target either CD8+ T(-ALL) cells  or Clec9A+ dendritic cells.
Results
Using CD8- and CD8+ mouse T-ALL cell lines, we evaluated the direct and indirect anti-leukemic effects of our novel AFNs, in vitro and in vivo upon transplantation in immunocompromised and immunocompetent syngeneic hosts. A significant reduction in the leukemic burden was observed. These anti-cancer effects of AFN were similar as observed for the wildtype IFN, but in a cell-type specific manner and with drastically reduced adverse side-effects. Monotherapy was even sufficient to completely cure a proportion of leukemic mice, which highlights the strong anti-leukemic power of these optimized immunocytokines. Strinkingly only the direct effect CD8-AFN on in vivo CD8+ T-ALL was synergistic with asparaginase treatment. No synergism was observed between asparaginase and the indirect immune-mediated Clec9A-AFN anti-leukemic effect.
Conclusion
In conclusion, we have developed novel optimized immunocytokines as an off-the-shelve targeted immunotherapy for T-ALL.},
  author       = {Goossens, Steven and Cauwels, Anje and Pieters, Tim and Daneels, Willem and Van Vlierberghe, Pieter and Tavernier, Jan},
  booktitle    = {EHA Library},
  language     = {und},
  publisher    = {European Hematology Association},
  title        = {TEACHING AN OLD DOG NEW TRICKS: ACTIVITY-ON-TARGET INTERFERON TO TREAT T-ALL},
  year         = {2020},
}