Mathematical Model Approach to Describe Tumour Response in Mice After Vaccine Administration and its Applicability to Immune-Stimulatory Cytokine-Based Strategies
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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.
Key wordscancer vaccine and mice immunotherapy mathematical modelling population approach
ZPP-G was supported by FPU fellowship from the Spanish Ministerio de Educacion, Cultura y Deporte and a grant from INRIA. PB was supported by a Miguel Servet contract from Spanish Fondo de Investigacion Sanitaria. This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 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 supported by financial contribution from Academic and SME partners. This work does not necessarily represent the view of all DDMoRe partners.
- 26.Beal S, Sheiner L, Boeckmann A. NONMEM Users Guide. Icon Development Solutions. 1989–2006.Google Scholar
- 41.Romero E, de Mendizabal NV, Cendrós JM, Peraire C, Bascompta E, Obach R, et al. Pharmacokinetic/pharmacodynamic model of the testosterone effects of triptorelin administered in sustained release formulations in patients with prostate cancer. J Pharmacol Exp Ther. 2012;342:788–98.PubMedCrossRefGoogle Scholar
- 44.Dobrzanski M, Rewers Felkins K, Samad K, Quinlin I, Phillips C, Robinson W, et al. Immunotherapy with IL-10- and IFN-γ-producing CD4 effector cells modulate “Natural” and “Inducible” CD4 TReg cell subpopulation levels: observations in four cases of patients with ovarian cancer. Cancer Immunol Immunother. 2012;61:839–54.PubMedCrossRefGoogle Scholar
- 45.Sakakibara M, Kanto T, Hayakawa M, Kuroda S, Miyatake H, Itose I, et al. Comprehensive immunological analyses of colorectal cancer patients in the phase I/II study of quickly matured dendritic cell vaccine pulsed with carcinoembryonic antigen peptide. Cancer Immunol Immunother. 2011;60:1565–75.PubMedCrossRefGoogle Scholar