Objectives. The aims of this work were (i) to develop a semi-mechanistic pharmacodynamic model describing tumour shrinkage after administration of a previously developed antitumour vaccine (CyaA-E7) in combination with CpG (a TLR9 ligand) and/or cyclophosphamide (CTX), and (ii) to assess the translational capability of the model to describe tumour effects of different immune-based reatments. Methods. Population approach with NONMEM v7.2 was used to analyze the previously published data. These data were generated injecting 5x105 tumour cells expressing HPV-E7 proteins to C57BL/6 mice. Large and established tumours 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 pre- and clinical outcomes obtained from literature. Results. CpG effects were modelled as (i) an amplification of the immune signal triggered by the vaccine and (ii) by shortening the delayed response of the vaccine. CTX effects were included through a direct decrease of the tumour-induced inhibition of vaccine efficacy over time, along with a delayed induction of tumour cell death. The model developed described the data in all combination scenarios, and was applied to successfully reproduce clinical outcomes when CpG or CTX were used in combination with different vaccines. Conclusions. A pharmacodynamic model, built based on plausible biological mechanisms known for the co-adjuvants, successfully characterized tumour response in all experimental scenarios. The results found after simulation exercise indicated that the contribution of the co-adjuvants to the tumour response elicited by vaccines can be predicted for other immune-based treatments.
- The American Society for Pharmacology and Experimental Therapeutics