TY - JOUR T1 - An Integrated Disease/Pharmacokinetic/Pharmacodynamic Model Suggests Improved Interleukin-21 Regimens Validated Prospectively for Mouse Solid Cancers A1 - Elishmereni, Moran A1 - Kheifetz, Yuri A1 - Søndergaard, Henrik A1 - Overgaard, Rune Viig A1 - Agur, Zvia Y1 - 2011/09/29 N2 - Author Summary Among the many potential drugs explored within the scope of cancer immunotherapy are selected cytokines which possess promising immune-boosting properties. Yet, the natural involvement of these proteins in multiple, often contradicting biological processes can complicate their use in the clinic. The cytokine interleukin (IL)-21 is no exception: while its strength as an anticancer agent has been established in several animal studies, response rates in melanoma and renal cell carcinoma patients remain low. To help guide the design of effective IL-21 therapy, we have developed a mathematical model that bridges between the complex biology of IL-21 and its optimal clinical use. Our model integrates data from preclinical studies under diverse IL-21 treatment settings, and was validated by extensive experiments in tumor-bearing mice. Model simulations predicted that beneficial, clinically practical IL-21 therapy should be composed of low-dose schedules, and/or schedules in which several partial doses are administered rather than a single complete dose. These findings were subsequently confirmed in mice with melanoma. Thus, future testing of these strategies in solid cancer patients can be a promising starting point for improving IL-21 therapy. Our model can thus provide a computational platform for rationalizing IL-21 regimens and streamlining its clinical development. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 7 IS - 9 UR - https://doi.org/10.1371/journal.pcbi.1002206 SP - e1002206 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1002206 ER -