Modeling tumor response after combined administration of different immune-stimulatory agents

The aims of this work were as follows: 1) to develop a semimechanistic pharmacodynamic model describing tumor shrinkage after administration of a previously developed antitumor vaccine (CyaA-E7) in combination with CpG (a TLR9 ligand) and/or cyclophosphamide (CTX), and 2) to assess the translational capability of the model to describe tumor effects of different immune-based treatments. Population approach with NONMEM version 7.2 was used to analyze the previously published data. These data were generated by injecting 5 × 10(5) tumor cells expressing human papillomavirus (HPV)-E7 proteins into C57BL/6 mice. Large and established tumors were treated with CpG and/or CTX administered alone or in combination with CyaA-E7. Applications of the model were assessed by comparing model-based simulations with preclinical and clinical outcomes obtained from literature. CpG effects were modeled: 1) as an amplification of the immune signal triggered by the vaccine and 2) by shortening the delayed response of the vaccine. CTX effects were included through a direct decrease of the tumor-induced inhibition of vaccine efficacy over time, along with a delayed induction of tumor cell death. A pharmacodynamic model, built based on plausible biologic mechanisms known for the coadjuvants, successfully characterized tumor response in all experimental scenarios. The model developed was satisfactory applied to reproduce clinical outcomes when CpG or CTX was used in combination with different vaccines. The results found after simulation exercise indicated that the contribution of the coadjuvants to the tumor response elicited by vaccines can be predicted for other immune-based treatments.