title: Mathematical model approach to describe tumour response in mice after vaccine administration and its applicability to immune-stimulatory cytokine-based strategies.
abstract: Immunotherapy is a growing therapeutic strategy in oncology based on the stimulation of innate and adaptive immune systems to induce the death of tumour cells. In this paper, we have developed a population semi-mechanistic model able to characterize the mechanisms implied in tumour growth dynamic after the administration of CyaA-E7, a vaccine able to target antigen to dendritic cells, thus triggering a potent immune response. The mathematical model developed presented the following main components: (1) tumour progression in the animals without treatment was described with a linear model, (2) vaccine effects were modelled assuming that vaccine triggers a non-instantaneous immune response inducing cell death. Delayed response was described with a series of two transit compartments, (3) a resistance effect decreasing vaccine efficiency was also incorporated through a regulator compartment dependent upon tumour size, and (4) a mixture model at the level of the elimination of the induced signal vaccine (k 2) to model tumour relapse after treatment, observed in a small percentage of animals (15.6%). The proposed model structure was successfully applied to describe antitumor effect of IL-12, suggesting its applicability to different immune-stimulatory therapies. In addition, a simulation exercise to evaluate in silico the impact on tumour size of possible combination therapies has been shown. This type of mathematical approaches may be helpful to maximize the information obtained from experiments in mice, reducing the number of animals and the cost of developing new antitumor immunotherapies.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/Irunlarrea 1, 31008, Pamplona, Navarra, Spain.
authors.forename: Zinnia P
authors.initials: ZP
authors.lastname: Parra-Guillen
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Grenier
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ribba
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Troconiz
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines