title: Optimization of interleukin-21 immunotherapeutic strategies.
abstract: The recently discovered interleukin-21 (IL-21) shows strong tumor attenuation in preclinical studies, and is considered a promising cancer immunotherapy agent. Yet, to exploit its potential, therapeutic strategies must be designed to achieve adequate balance between several conflicting aspects. A mathematical model describing the IL-21-antitumor effects provided the basis for application of the optimization methodology, aimed at finding improved immunotherapeutic regimens. Both dosages and inter-dosing intervals were optimized while considering maximal efficacy, determined by reduction of tumor burden, and minimal toxicity, estimated by cumulative IL-21 doses applied. Simulations allowed to compute the optimal regimen and explore its dependence on the weights of the target function. Optimized schedules lead to substantial cancer regression even with relatively low drug concentrations. Collectively, administration times shifted towards treatment onset, and IL-21 intensities sequentially decreased. Interestingly, there was a certain window in which deviations in the total IL-21 dosage administered largely influenced tumor elimination. The findings emphasize the importance of early tumor detection and the critical consequence of the inter-dosing interval on therapeutic efficacy, as supported by similar research involving chemotherapy. Our work provides initial basis for identifying clinically applicable IL-21 therapeutic strategies with improved efficacy/toxicity ratios.
authors.affiliation: Institute for Medical Biomathematics (IMBM), P.O.B. 282, Hate'ena St. 10, Bene-Ataroth 60991, Israel.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cappuccio
authors.forename: Moran
authors.initials: M
authors.lastname: Elishmereni
authors.forename: Zvia
authors.initials: Z
authors.lastname: Agur
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003198:Computer Simulation; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007378:Interleukins / Q000627:therapeutic use*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D000098546:Interleukin-21
chemical_list: D000970:Antineoplastic Agents; D007378:Interleukins; D000098546:Interleukin-21