Optimization of virotherapy for cancer.

Several viruses preferentially infect and replicate in cancer cells by usurping pathways that are defective in the tumor cell population. Such viruses have a potential as oncolytic agents. The aim of tumor virotherapy is that after injection of the replicating virus, it propagates in the tumor cell population with amplification. As a result, the oncolytic virus spreads to eradicate the tumor. The outcome of tumor virotherapy is determined by population dynamics and different from standard cancer therapy. Several models have been developed that provided considerable insights on the potential therapeutic scenarios. However, virotherapy is potentially risky since large amounts of a replicating virus are injected in the host with a risk of adverse effects. Therefore, the optimal dose, number of doses, and timing are expected to play an important role on the outcome both for the tumor and the host. In the current work, we combine a model of the dynamics of tumor virotherapy that was validated with experimental data with optimization theory to illustrate how we can improve the outcome of tumor therapy. In this first report, we demonstrate that (i) in most circumstances, anything more than two administrations of a vector is not helpful, (ii) correctly timed delivery of the virus provides superior results compared to regularly scheduled therapy or continuous infusion, (iii) a second dose of virus that is not properly timed leads to a worse outcome compared to a single dose of virus, and (iv) it is less costly to treat larger tumors.