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

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

Stochastic modeling of kHz quasi-periodic oscillation light curves

Aims.Kluźniak & Abramowicz explain the high frequency, double peak, “3:2” QPOs observed in neutron star and black hole sources in terms of a non-linear parametric resonance between radial and vertical epicyclic oscillations of an almost Keplerian accretion disk. The 3:2 ratio of epicyclic frequencies occurs only in strong gravity. Recently, a simple model incorporating their suggestion was studied analytically: the result is that a small forcing may indeed excite the parametric 3:2 resonance. However, no explanation has been provided on the nature of the forcing which is given an “ad hoc” deterministic form. Methods.In the present paper the same model is considered. The equation are numerically integrated, dropping the ad hoc forcing and adding instead a stochastic term to mimic the action of the very complex processes that occur in accretion disks as, for example, MRI turbulence. Results.We demonstrate that the presence of the stochastic term is able to trigger the resonance in epicyclic oscillations of nearly Keplerian disks, and it influences their pattern