A QSP Model of Prostate Cancer Immunotherapy to Identify Effective Combination Therapies - Beyond the Abstract

Immunotherapy 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.


A recent study published in Scientific Reports, "A QSP Model of Prostate Cancer Immunotherapy to Identify Effective Combination Therapies", provides a mathematical model of prostate cancer calibrated on data from pre-clinical experiments in prostate cancer mouse models. The model, which has been developed by using ordinary differential equations, describes the evolution of prostate cancer and key components of the immune system. The model also includes seven treatments: androgen deprivation therapy, dendritic vaccine, anti-IL-2, anti-Treg, anti-MDSCs, NK infusion, and immune checkpoint blockade drugs (ICB), which have been combined to evaluate the most promising combination therapy by considering both the predicted tumor reduction and the synergistic properties between the treatments. This information has been integrated into a decision tree, which investigates the immunotherapy effects on the castration-resistant prostate cancer form, in those cases in which the androgen-independent prostate cancer proliferates after the androgen deprivation therapy.

Compared with the previous prostate cancer mathematical models, this work includes more mechanistic details about the tumor microenvironment. These extensions allow the authors to test different types of immunotherapy, proposing a cost-effective approach to identify in silico the most promising combination therapies. The numerical simulations provided in this paper predict immune checkpoint blockade (ICB) as the most effective immunotherapy in subjects under androgen deprivation therapy. Supporting this finding, a Phase II clinical trial testing the effect of an immune checkpoint blockade on patients previously treated with androgen deprivation therapy shows that these monoclonal antibodies may be able to block the tumor progression (NCT02312557). The model also highlights a synergistic effect between ICB and dendritic vaccine, which is predicted to be the most promising dual-drug therapy for patients developing the androgen-independent prostate cancer form. Interestingly, a combination therapy involving ICB and dendritic vaccine is currently under Phase II clinical trial (NCT01804465).

Overall, this work represents a computational framework to help drug development, by generating hypotheses that can be tested experimentally in preclinical models.

Written by: Roberta Coletti, Lorena Leonardelli, Silvia Parolo, Luca Marchetti

University of Trento, Department of mathematics, Trento, 38123, Italy., Fondazione The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, 38068, Italy., Fondazione The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, 38068, Italy. .

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