A Model-Based Framework to Identify Optimal Administration Protocols for Immunotherapies in Castration-Resistance Prostate Cancer

SIMPLE SUMMARY: Although ipilimumab has been approved for the treatment of many types of cancer, most prostate cancer patients seem to not respond well to the therapy. Here, we mathematically investigate the clinical relevance of ipilimumab, as mono-therapy and in combination with the dendritic cell vaccine sipuleucel-T, for the treatment of castration-resistant prostate cancer patients. The employed optimization problem, which incorporates a function of toxicity depending on the drug concentration, establishes precise protocols of administration of ipilimumab to control or eradicate prostate tumor, and defines how changing of key parameters affects the outcome. Overall, this mathematical study can help in optimizing the clinical use of ipilimumab for the effective treatment of castration-resistant prostate cancer patients. ABSTRACT: Prostate cancer (PCa) is one of the most frequent cancer in male population. Androgen deprivation therapy is the first-line strategy for the metastatic stage of the disease, but, inevitably, PCa develops resistance to castration (CRPC), becoming incurable. In recent years, clinical trials are testing the efficacy of anti-CTLA4 on CRPC. However, this tumor seems to be resistant to immunotherapies that are very effective in other types of cancers, and, so far, only the dendritic cell vaccine sipuleucel-T has been approved. In this work, we employ a mathematical model of CRPC to determine the optimal administration protocol of ipilimumab, a particular anti-CTLA4, as single treatment or in combination with the sipuleucel-T, by considering both the effect on tumor population and the drug toxicity. To this end, we first introduce a dose-depending function of toxicity, estimated from experimental data, then we define two different optimization problems. We show the results obtained by imposing different constraints, and how these change by varying drug efficacy. Our results suggest administration of high-doses for a brief period, which is predicted to be more efficient than solutions with prolonged low-doses. The model also highlights a synergy between ipilimumab and sipuleucel-T, which leads to a better tumor control with lower doses of ipilimumab. Finally, tumor eradication is also conceivable, but it depends on patient-specific parameters.