Cappuccio2006 - Cancer immunotherapy by interleukin-21

  public model
Model Identifier
BIOMD0000000761
Short description
This model describes the effects of Il-21 on tumor eradication via natural killer cell-mediated and CD8+ T-cell-mediated lysis of tumor cells. The model demonstrates changes in growth dynamics in nonimmunogenic B16 melanoma and the immunogenic MethA and MCA205 fibrosarcomas, showing a strong dependence of the NK-cell/CD8+ T-cell balance on tumor immunogenicity.
Format
SBML (L2V4)
Related Publication
  • Cancer immunotherapy by interleukin-21: potential treatment strategies evaluated in a mathematical model.
  • Cappuccio A, Elishmereni M, Agur Z
  • Cancer research , 7/ 2006 , Volume 66 , Issue 14 , pages: 7293-7300 , PubMed ID: 16849579
  • Institute for Medical Biomathematics, Bene-Ataroth, Israel.
  • The newly characterized interleukin (IL)-21 plays a central role in the transition from innate immunity to adaptive immunity and shows substantial tumor regression in mice. IL-21 is now developed as a cancer immunotherapeutic drug, but conditions for efficacious therapy, and the conflicting immunostimulatory and immunoinhibitory influence of the cytokine, are yet to be defined. We studied the effects of IL-21 on tumor eradication in a mathematical model focusing on natural killer (NK) cell-mediated and CD8+ T-cell-mediated lysis of tumor cells. Model parameters were estimated using results in tumor-bearing mice treated with IL-21 via cytokine gene therapy (CGT), hydrodynamics-based gene delivery (HGD), or standard interval dosing (SID). Our model accurately retrieved experimental growth dynamics in the nonimmunogenic B16 melanoma and the immunogenic MethA and MCA205 fibrosarcomas, showing a strong dependence of the NK-cell/CD8+ T-cell balance on tumor immunogenicity. Moreover, in melanoma, simulations of CGT-like dosing regimens, dynamically determined according to tumor mass changes, resulted in efficient disease elimination. In contrast, in fibrosarcoma, such a strategy was not superior to that of fixed dosing regimens, HGD or SID. Our model supports clinical use of IL-21 as a potent stimulator of cellular immunity against cancer, and suggests selecting the immunotherapy strategy according to tumor immunogenicity. Nonimmunogenic tumors, but not highly immunogenic tumors, should be controlled by IL-21 dosing, which depends on tumor mass at the time of administration. This method imitates, yet amplifies, the natural anticancer immune response rather than accelerates only one of the response arms in an unbalanced manner.
Contributors
Submitter of the first revision: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer

Metadata information

is (2 statements)
BioModels Database MODEL1907230001
BioModels Database BIOMD0000000761

isDescribedBy (1 statement)
PubMed 16849579

hasTaxon (1 statement)
Taxonomy Mus musculus

hasPart (2 statements)
hasProperty (3 statements)
Curation status
Curated
Modelling approach(es)
ordinary differential equation model
Tags
Immuno-oncology

Connected external resources

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Name Description Size Actions

Model files
Cappuccio2006 v2.0.xml L2V4 SBML Model of Cappuccio2006 - Cancer immunotherapy by interleukin-21 75.35 KB Preview | Download

Additional files
Cappuccio2006 v9.0.cps COPASI file of Model of Cappuccio2006 - Cancer immunotherapy by interleukin-21 94.33 KB Preview | Download
Cappuccio2006 v9.0.sedml SED-ML file of Model of Cappuccio2006 - Cancer immunotherapy by interleukin-21 1.71 KB Preview | Download

  • Model originally submitted by : Johannes Meyer
  • Submitted: Jul 26, 2019 9:19:34 AM
  • Last Modified: Jul 26, 2019 9:19:34 AM
Revisions
  • Version: 6 public model Download this version
    • Submitted on: Jul 26, 2019 9:19:34 AM
    • Submitted by: Johannes Meyer
    • With comment: Automatically added model identifier BIOMD0000000761
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
Z

Surface ; Tumor Mass 		2.0 nmol
P

Perforin 1 (Pore forming protein)Perforin 1 (Pore forming protein), isoform CRA a ; Interferon gamma 		0.0 nmol
M

Regulator 		0.0 nmol
X

natural killer cell ; spleen 		1.95185 nmol
Y

CD8-Positive T-Lymphocyte ; CD8-positive, alpha-beta thymocyte ; lymph node 		0.066 nmol
U

Interleukin-21 		0.0 nmol
Reactions
Reactions Rate Parameters
=> Z compartment*c c = 5.1 (mm^2)/d
P => compartment*mu3*P mu3 = 0.08 1/d
M => compartment*mu2*M mu2 = 0.014 1/d
=> X compartment*r1*X r1 = 0.095 1/d
Z => ; P, X compartment*k1*P*X*Z k1 = 0.05 ml/(d*nmol)
=> P; U compartment*b1*U/(b2+U) b2 = 0.1 nmol/ml; b1 = 1.0 nmol/(d*ml)
=> Z; Z compartment*Z^((-1)/2)*Z^(3/2)*10^(-6) []
X => ; X, U compartment*r1*X^2/((p1*U+p2)/(U+q1)) p1 = 0.01; p2 = 1.054; q1 = 0.54; r1 = 0.095 1/d
Y => ; M compartment*r2*Y^2/(h2zero+sigma*M/(1+M/D)) sigma = 0.003; h2zero = 0.066; r2 = 0.26 1/d; D = 1418.4
U => compartment*mu1*U mu1 = 10.0 1/d
Curator's comment:
(added: 23 Jul 2019, 13:36:59, updated: 23 Jul 2019, 13:36:59)
Reproduced plot of Figure 4A of the original publication. No changes were made to the original model to reproduce to the simulation result. Solved and plotted using COPASI 4.24 (Build 197).