Kronik2008 - Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics
Model Identifier
BIOMD0000000808
Short description
This mathematical model describes interactions between glioma tumors and the immune system that may occur following direct intra-tumoral administration of ex-vivo activated alloreactive cytotoxic-T-lymphocytes (aCTLs) as part of adoptive immunotherapy. The model includes descriptions of aCTL, neoplastic cells, MHC class I and II molecules, TGF-beta and IFN-gamma.
Format
SBML
(L2V4)
Related Publication
- Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics.
- Kronik N, Kogan Y, Vainstein V, Agur Z
- Cancer immunology, immunotherapy : CII , 3/ 2008 , Volume 57 , Issue 3 , pages: 425-439 , PubMed ID: 17823798
- Institute for Medical BioMathematics (IMBM), 10 Hate'ena St., PO Box 282, Bene Ataroth 60991, Israel. natalie@imbm.org
- Glioblastoma (GBM), a highly aggressive (WHO grade IV) primary brain tumor, is refractory to traditional treatments, such as surgery, radiation or chemotherapy. This study aims at aiding in the design of more efficacious GBM therapies. We constructed a mathematical model for glioma and the immune system interactions, that may ensue upon direct intra-tumoral administration of ex vivo activated alloreactive cytotoxic-T-lymphocytes (aCTL). Our model encompasses considerations of the interactive dynamics of aCTL, tumor cells, major histocompatibility complex (MHC) class I and MHC class II molecules, as well as cytokines, such as TGF-beta and IFN-gamma, which dampen or increase the pro-inflammatory environment, respectively. Computer simulations were used for model verification and for retrieving putative treatment scenarios. The mathematical model successfully retrieved clinical trial results of efficacious aCTL immunotherapy for recurrent anaplastic oligodendroglioma and anaplastic astrocytoma (WHO grade III). It predicted that cellular adoptive immunotherapy failed in GBM because the administered dose was 20-fold lower than required for therapeutic efficacy. Model analysis suggests that GBM may be eradicated by new dose-intensive strategies, e.g., 3 x 10(8) aCTL every 4 days for small tumor burden, or 2 x 10(9) aCTL, infused every 5 days for larger tumor burden. Further analysis pinpoints crucial bio-markers relating to tumor growth rate, tumor size, and tumor sensitivity to the immune system, whose estimation enables regimen personalization. We propose that adoptive cellular immunotherapy was prematurely abandoned. It may prove efficacious for GBM, if dose intensity is augmented, as prescribed by the mathematical model. Re-initiation of clinical trials, using calculated individualized regimens for grade III-IV malignant glioma, is suggested.
Contributors
Submitter of the first revision: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Metadata information
is (2 statements)
isDescribedBy (1 statement)
hasProperty (2 statements)
isDescribedBy (1 statement)
hasProperty (2 statements)
Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
Name | Description | Size | Actions |
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Model files |
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Kronik2008.xml | SBML L2V4 Representation of Kronik2008 - Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics | 96.85 KB | Preview | Download |
Additional files |
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Kronik2008.cps | COPASI file of Kronik2008 - Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics | 117.38 KB | Preview | Download |
Kronik2008.sedml | SED-ML file of Kronik2008 - Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics | 2.25 KB | Preview | Download |
- Model originally submitted by : Johannes Meyer
- Submitted: Sep 9, 2019 9:08:22 AM
- Last Modified: Sep 9, 2019 9:08:22 AM
Revisions
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
Species | Initial Concentration/Amount |
---|---|
F beta Transforming Growth Factor-Beta Superfamily |
0.0 mmol |
T neoplastic cell |
1.0E10 mmol |
M1 MHC class I protein complex |
0.0 mmol |
C cytotoxic T cell |
2000000.0 mmol |
F gamma Interferon gamma |
0.0 mmol |
Reactions
Reactions | Rate | Parameters |
---|---|---|
=> F_beta; T | compartment*a_T_beta*T | a_T_beta = 0.69 |
=> T | compartment*r*T*(1-T/K) | K = 1.0E11; r = 3.5E-4 |
M1 => | compartment*mu_M1*M1 | mu_M1 = 0.0144 |
T => ; M1, C, F_beta | compartment*a_T*M1/(M1+e_T)*C*T/(h_T+T)*(a_T_beta+e_T_beta*(1-a_T_beta)/(F_beta+e_T_beta)) | e_T_beta = 10000.0; a_T_beta = 0.69; a_T = 0.12; e_T = 50.0; h_T = 5.0E8 |
C => | compartment*mu_C*C | mu_C = 0.007 |
=> M1 | compartment*v | v=0.1 |
F_beta => | compartment*mu_beta*F_beta | mu_beta = 7.0 |
F_gamma => | compartment*mu_gamma*F_gamma | mu_gamma = 0.102 |
=> F_beta | compartment*g_beta | g_beta = 63945.0 |
Curator's comment:
(added: 09 Sep 2019, 09:08:12, updated: 09 Sep 2019, 09:08:12)
(added: 09 Sep 2019, 09:08:12, updated: 09 Sep 2019, 09:08:12)
Reproduced plot of Figure 2B in the original publication. X-axis is in hours. Initial conditions and parameter values are as indicated in the paper, except for the value of r, which was changed from 0.00035 to 0.0035.
Model simulated and plot produced using COPASI 4.24 (Build 197).