Population semi-mechanistic modelling of tumour response elicited by Immune-stimulatory based therapeutics in mice
Zinnia P Parra-Guillen (1), Pedro Berraondo (2), Emmanuel Grenier (3), Benjamin Ribba (4) and Iñaki F Troconiz (1)
(1) Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra. Pamplona (Spain), (2) Division of Hepatology and Gene Therapy, Centre for Applied Medical Research, University of Navarra. Pamplona (Spain), (3) INRIA Rhône-Alpes, Project-team NUMED, Ecole Normale Supérieure de Lyon. Lyon (France), (4) INRIA Grenoble-Rhône-Alpes, Project-team NUMED. Saint Ismier (France)
Objectives: Quantitative analysis applying population pharmacokinetic/ pharmacodynamic principles is still scarce in the area of immunotherapy especially in pre-clinical tumour models. The aim of this work was (i) to develop a semi-mechanistic population pharmacodynamic model to describe the effects of a vaccine (CyaA-E7) able to trigger a potent and specific immune response in xenografts mice, and (ii) to assess the applicability of the model under different immune-base treatments.
Methods: Data published previously were used . Briefly, 5x105 tumour cells expressing HPV-E7 protein were injected in C57BL/6 mice (day 0) and a single 50 µg dose of CyaA-E7 vaccine was administered intravenously either on day 4, 7, 11, 18, 25 or 30. For the combination studies, 50 µg of CyaA-E7 in combination with 30 µg of CpG (a TLR ligand) and/or 2.5 mg of cyclophosphamide (CTX) on the previous day were given on days 25, 30 or 40. Additional groups of mice receiving PBS on day 4 or CPG or/and CTX on day 25 and 24 respectively were also included. Applicability of the model was tested using published data with IL12 as immunotherapeutic agent . All analyses were performed in NONMEM 7.2. Bootstrap analysis, visual and numerical predictive checks were generated to evaluate the model.
Results: The final model had the following features: (i) Tumour growth independent of tumour size (Ts), (ii) a K-PD model  describing vaccine effects over Ts through a delayed and permanent vaccine signal (SVAC), (iii) a Treg cells compartment controlled by Ts and able to inhibit vaccine efficacy to account for the decrease in vaccine response, and (v) finally, the existence of a subpopulation (mixture model ) of mice where only a temporal tumour response was triggered. CpG effects were modelled as an amplification of the immune signal triggered by the vaccine, shortening in addition its delay with respect time, and CTX effects were included through a direct decrease in the Treg synthesis process, along with a delayed induction of tumour cell death. CyaA-E7, CpG and CTX models were coupled to simulate tumour size profiles corresponding to the tritherapy administration on days 25, 30 and 40 resulting in a very good description of the data. Moreover, the model was capable to successfully describe data outcome after IL-12-based immune-stimulatory study without any further structural modification.
Conclusions: This work presents a novel mathematical model were different modelling strategies such as censored data or mixture model have been integrated to successfully describe different immunotherapeutic strategies. This model can be used to maximize the information obtained from preclinical settings, optimizing the design of clinical trials of immune modulating drugs.
Aknowlegments: The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115156, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. The DDMoRe project is also financially supported by contributions from Academic and SME partners
 Berraondo P et al. Cancer Res 67: 8847-55, 2007.
 Medina-Echeverz J et al. J Immunol 186:807-15, 2011.
 Jacqmin P et al. J Pharmacokinet Pharmacodyn 34:57-85, 2007.
 Carlsson KC et al. AAPS J 11:148-54, 2009.