An Integrated Disease/Pharmacokinetic/Pharmacodynamic Model Suggests Improved Interleukin-21 Regimens Validated Prospectively for Mouse Solid Cancers

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Abstract
Interleukin (IL)-21 is an attractive antitumor agent with potent immunomodulatory functions. Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive. The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses. For this purpose, pharmacokinetic (PK) and pharmacodynamic (PD) data were acquired from a preclinical study applying systemic IL-21 therapy in murine solid cancers. We developed an integrated disease/PK/PD model for the IL-21 anticancer response, and calibrated it using selected “training” data. The accuracy of the model was verified retrospectively under diverse IL-21 treatment settings, by comparing its predictions to independent “validation” data in melanoma and renal cell carcinoma-challenged mice (R2>0.90). Simulations of the verified model surfaced important therapeutic insights: (1) Fractionating the standard daily regimen (50 µg/dose) into a twice daily schedule (25 µg/dose) is advantageous, yielding a significantly lower tumor mass (45% decrease); (2) A low-dose (12 µg/day) regimen exerts a response similar to that obtained under the 50 µg/day treatment, suggestive of an equally efficacious dose with potentially reduced toxicity. Subsequent experiments in melanoma-bearing mice corroborated both of these predictions with high precision (R2>0.89), thus validating the model also prospectively in vivo. Thus, the confirmed PK/PD model rationalizes IL-21 therapy, and pinpoints improved clinically-feasible treatment schedules. Our analysis demonstrates the value of employing mathematical modeling and in silico-guided design of solid tumor immunotherapy in the clinic. 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.