A QSP model of prostate cancer immunotherapy to identify effective combination therapies

• Published in: Scientific reports 2020-06, Vol.10 (1), p.9063-9063, Article 9063
• Main Authors: Coletti, Roberta, Leonardelli, Lorena, Parolo, Silvia, Marchetti, Luca
• Format: Article
• Language: English
• Subjects: 119/118; 631/114/2397; 631/553/2700; 631/67/1059/2325; 631/67/589/466; 692/4028/67/589/466; Animal models; Animals; Cancer immunotherapy; Cancer therapies; Cancer vaccines; Cancer Vaccines - immunology; Castration; Cell Line, Tumor; Combined Modality Therapy - methods; Combined vaccines; Computer applications; Differential equations; Drug development; Humanities and Social Sciences; Humans; Immune checkpoint; Immune response; Immune system; Immunologic Factors - immunology; Immunotherapy; Immunotherapy - methods; Male; Mice; Models, Biological; multidisciplinary; Ordinary differential equations; Pharmacology; Prostate - immunology; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - immunology; Prostatic Neoplasms, Castration-Resistant - therapy; Science; Science (multidisciplinary); Synergistic effect
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-65590-0

Immunotherapy, by enhancing the endogenous anti-tumor immune responses, is showing promising results for the treatment of numerous cancers refractory to conventional therapies. However, its effectiveness for advanced castration-resistant prostate cancer remains unsatisfactory and new therapeutic strategies need to be developed. To this end, systems pharmacology modeling provides a quantitative framework to test in silico the efficacy of new treatments and combination therapies. In this paper we present a new Quantitative Systems Pharmacology (QSP) model of prostate cancer immunotherapy, calibrated using data from pre-clinical experiments in prostate cancer mouse models. We developed the model by using Ordinary Differential Equations (ODEs) describing the tumor, key components of the immune system, and seven treatments. Numerous combination therapies were evaluated considering both the degree of tumor inhibition and the predicted synergistic effects, integrated into a decision tree. Our simulations predicted cancer vaccine combined with immune checkpoint blockade as the most effective dual-drug combination immunotherapy for subjects treated with androgen-deprivation therapy that developed resistance. Overall, the model presented here serves as a computational framework to support drug development, by generating hypotheses that can be tested experimentally in pre-clinical models.