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Modeling the competition between lung metastases and the immune system using agents.

Pennisi M, Pappalardo F, Palladini A, Nicoletti G, Nanni P, Lollini PL, Motta S - BMC Bioinformatics (2010)

Bottom Line: Such a reduction may represent an important result from the point of view of translational medicine to humans, since a downsizing of the number of vaccinations is usually advisable in order to minimize undesirable effects.Even if this strategy is commonly used for many infectious diseases such as tetanus and hepatitis-B, it can be in fact considered as a relevant result in the field of cancer-vaccines immunotherapy.These results can be then used and verified in future "in vivo" experiments, and their outcome can be used to further improve and refine the model.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Mathematics and Computer Science, University of Catania, V,le A, Doria 6, Catania, Italy. mpennisi@dmi.unict.it

ABSTRACT

Background: The Triplex cell vaccine is a cancer cellular vaccine that can prevent almost completely the mammary tumor onset in HER-2/neu transgenic mice. In a translational perspective, the activity of the Triplex vaccine was also investigated against lung metastases showing that the vaccine is an effective treatment also for the cure of metastases. A future human application of the Triplex vaccine should take into account several aspects of biological behavior of the involved entities to improve the efficacy of therapeutic treatment and to try to predict, for example, the outcomes of longer experiments in order to move faster towards clinical phase I trials. To help to address this problem, MetastaSim, a hybrid Agent Based - ODE model for the simulation of the vaccine-elicited immune system response against lung metastases in mice is presented. The model is used as in silico wet-lab. As a first application MetastaSim is used to find protocols capable of maximizing the total number of prevented metastases, minimizing the number of vaccine administrations.

Results: The model shows that it is possible to obtain "in silico" a 45% reduction in the number of vaccinations. The analysis of the results further suggests that any optimal protocol for preventing lung metastases formation should be composed by an initial massive vaccine dosage followed by few vaccine recalls.

Conclusions: Such a reduction may represent an important result from the point of view of translational medicine to humans, since a downsizing of the number of vaccinations is usually advisable in order to minimize undesirable effects. The suggested vaccination strategy also represents a notable outcome. Even if this strategy is commonly used for many infectious diseases such as tetanus and hepatitis-B, it can be in fact considered as a relevant result in the field of cancer-vaccines immunotherapy. These results can be then used and verified in future "in vivo" experiments, and their outcome can be used to further improve and refine the model.

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Comparison of behaviors using 1+Triplex and Protocol 87. Mean dynamics of relevant entities in untreated (red line) and treated mice using Triplex+1 (blue line), Triplex+7 (green line) and protocol 87 (purple line). From left to right, up to down: Cancer cells (CC) (a), B cells (B) (b), TH cells (TH) (c), TC cells (TC) (d), macrophages (MP) (e), interleukin-2 (IL-2) (f), interleukin-12 (IL-12) (g) and interferon-γ (INF-g) (h). CC, Ag, IL-2, IL-12 and INF-g plots are presented on a logarithmic scale to improve comparison.
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Figure 4: Comparison of behaviors using 1+Triplex and Protocol 87. Mean dynamics of relevant entities in untreated (red line) and treated mice using Triplex+1 (blue line), Triplex+7 (green line) and protocol 87 (purple line). From left to right, up to down: Cancer cells (CC) (a), B cells (B) (b), TH cells (TH) (c), TC cells (TC) (d), macrophages (MP) (e), interleukin-2 (IL-2) (f), interleukin-12 (IL-12) (g) and interferon-γ (INF-g) (h). CC, Ag, IL-2, IL-12 and INF-g plots are presented on a logarithmic scale to improve comparison.

Mentions: Results also show that it is possible, using protocols 87 and 103, to achieve "in silico" (with just 5 injections) the same protection elicited by the 9-injections protocol "Triplex+1". Figure 4 summarizes the mean behaviors (computed on 100 mice) for the most important entities in mice without treatment, using protocols "Triplex+1", "Triplex+7" and protocol 87 which consists of 5 injections. From figure 4 it is possible to see that the 5-injections protocol 87 is able to entitle similar immune response as the "Triplex+1" protocol. B lymphocytes (B) (b), cytotoxic T cells (TC) (d), T helper cells (TH) (c), and Macrophages (MP) (e) plots show how the vaccine is able to favor immune system responses thanks to the earlier appearance of the antigen (Ag) and of interleukin 12 (IL-12) (g). Also interleukin 2 (IL-2) (f) appears earlier and in greater quantities. The lack of the initial two injections shows how the "chemotaxis-driven" stronger immune response entitled with the use of protocol "Triplex+7" (see in particular the cytotoxic T cells dynamics, boosted also by the "TC activation" interaction with a bigger number of Cancer Cells) is however unable to effectively deal with the exponential growth of the metastatic nodules.


Modeling the competition between lung metastases and the immune system using agents.

Pennisi M, Pappalardo F, Palladini A, Nicoletti G, Nanni P, Lollini PL, Motta S - BMC Bioinformatics (2010)

Comparison of behaviors using 1+Triplex and Protocol 87. Mean dynamics of relevant entities in untreated (red line) and treated mice using Triplex+1 (blue line), Triplex+7 (green line) and protocol 87 (purple line). From left to right, up to down: Cancer cells (CC) (a), B cells (B) (b), TH cells (TH) (c), TC cells (TC) (d), macrophages (MP) (e), interleukin-2 (IL-2) (f), interleukin-12 (IL-12) (g) and interferon-γ (INF-g) (h). CC, Ag, IL-2, IL-12 and INF-g plots are presented on a logarithmic scale to improve comparison.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2957681&req=5

Figure 4: Comparison of behaviors using 1+Triplex and Protocol 87. Mean dynamics of relevant entities in untreated (red line) and treated mice using Triplex+1 (blue line), Triplex+7 (green line) and protocol 87 (purple line). From left to right, up to down: Cancer cells (CC) (a), B cells (B) (b), TH cells (TH) (c), TC cells (TC) (d), macrophages (MP) (e), interleukin-2 (IL-2) (f), interleukin-12 (IL-12) (g) and interferon-γ (INF-g) (h). CC, Ag, IL-2, IL-12 and INF-g plots are presented on a logarithmic scale to improve comparison.
Mentions: Results also show that it is possible, using protocols 87 and 103, to achieve "in silico" (with just 5 injections) the same protection elicited by the 9-injections protocol "Triplex+1". Figure 4 summarizes the mean behaviors (computed on 100 mice) for the most important entities in mice without treatment, using protocols "Triplex+1", "Triplex+7" and protocol 87 which consists of 5 injections. From figure 4 it is possible to see that the 5-injections protocol 87 is able to entitle similar immune response as the "Triplex+1" protocol. B lymphocytes (B) (b), cytotoxic T cells (TC) (d), T helper cells (TH) (c), and Macrophages (MP) (e) plots show how the vaccine is able to favor immune system responses thanks to the earlier appearance of the antigen (Ag) and of interleukin 12 (IL-12) (g). Also interleukin 2 (IL-2) (f) appears earlier and in greater quantities. The lack of the initial two injections shows how the "chemotaxis-driven" stronger immune response entitled with the use of protocol "Triplex+7" (see in particular the cytotoxic T cells dynamics, boosted also by the "TC activation" interaction with a bigger number of Cancer Cells) is however unable to effectively deal with the exponential growth of the metastatic nodules.

Bottom Line: Such a reduction may represent an important result from the point of view of translational medicine to humans, since a downsizing of the number of vaccinations is usually advisable in order to minimize undesirable effects.Even if this strategy is commonly used for many infectious diseases such as tetanus and hepatitis-B, it can be in fact considered as a relevant result in the field of cancer-vaccines immunotherapy.These results can be then used and verified in future "in vivo" experiments, and their outcome can be used to further improve and refine the model.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Mathematics and Computer Science, University of Catania, V,le A, Doria 6, Catania, Italy. mpennisi@dmi.unict.it

ABSTRACT

Background: The Triplex cell vaccine is a cancer cellular vaccine that can prevent almost completely the mammary tumor onset in HER-2/neu transgenic mice. In a translational perspective, the activity of the Triplex vaccine was also investigated against lung metastases showing that the vaccine is an effective treatment also for the cure of metastases. A future human application of the Triplex vaccine should take into account several aspects of biological behavior of the involved entities to improve the efficacy of therapeutic treatment and to try to predict, for example, the outcomes of longer experiments in order to move faster towards clinical phase I trials. To help to address this problem, MetastaSim, a hybrid Agent Based - ODE model for the simulation of the vaccine-elicited immune system response against lung metastases in mice is presented. The model is used as in silico wet-lab. As a first application MetastaSim is used to find protocols capable of maximizing the total number of prevented metastases, minimizing the number of vaccine administrations.

Results: The model shows that it is possible to obtain "in silico" a 45% reduction in the number of vaccinations. The analysis of the results further suggests that any optimal protocol for preventing lung metastases formation should be composed by an initial massive vaccine dosage followed by few vaccine recalls.

Conclusions: Such a reduction may represent an important result from the point of view of translational medicine to humans, since a downsizing of the number of vaccinations is usually advisable in order to minimize undesirable effects. The suggested vaccination strategy also represents a notable outcome. Even if this strategy is commonly used for many infectious diseases such as tetanus and hepatitis-B, it can be in fact considered as a relevant result in the field of cancer-vaccines immunotherapy. These results can be then used and verified in future "in vivo" experiments, and their outcome can be used to further improve and refine the model.

Show MeSH
Related in: MedlinePlus