Combining Androgen Deprivation and Immunotherapy in Prostate Cancer Treatment: A Mechanistic Approach

Abstract

Due to its initial dependence on testosterone, prostate cancer patients are initially treated with androgen deprivation therapy, a form of chemical castration. However, in many cases, the cancer develops resistance to this treatment. Sipuleucel-T (Provenge), is the first live cell vaccine approved for treating patients with advanced, hormonally refractive prostate cancer. However, it has shown limited survival benefit. Recently, it has been proposed that combining Provenge with androgen deprivation may result in a better treatment outcome. Here, we develop a nonlinear dynamical systems model with a view to predicting the therapeutic potential of such a combination. Our model accounts for the mechanism of action of Provenge and the immune system response elicited by androgen deprivation. We use data from mouse xenograft experiments to calibrate and validate our model. The validated model is then used to explain the limited clinical success of Provenge, and predict optimal scheduling that maximizes the anti-tumor potential of Provenge combined with androgen deprivation. In particular, we demonstrate that the two treatments should be given concurrently, rather than sequentially, as is current practice.