Leon-Triana2021 - Competition between tumour cells and single-target CAR T-cells

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Model Identifier
BIOMD0000001013
Short description
This model of the use of chimeric antigen receptor (CAR)-T cell therapy in the treatment of solid tumours is described in the article:
"Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept"
Odelaisy León-Triana, Antonio Pérez-Martínez, Manuel Ramírez-Orellana and Víctor M. Pérez-García
Cancers 2021, 13, 703.; doi: 10.3390/cancers13040703

Comment:
This is the first mathematical model, derived from equations 1 and 2, used in the paper.
Reproduction of Fig. 5a was achieved by setting alpha_1 = 0.04, different to the value quoted in the article caption for Fig. 5.

Abstract:
Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments.
Format
SBML (L2V4)
Related Publication
  • Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept.
  • León-Triana O, Pérez-Martínez A, Ramírez-Orellana M, Pérez-García VM
  • Cancers , 2/ 2021 , Volume 13 , Issue 4 , PubMed ID: 33572301
  • Mathematical Oncology Laboratory (MOLAB), Department of Mathematics, Instituto de Matemática Aplicada a la Ciencia y la Ingeniería, Universidad de Castilla-La Mancha, Avda. Camilo José Cela, 3, 13071 Ciudad Real, Spain.
  • Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments.
Contributors
Emilia Chen

Metadata information

hasTaxon
Taxonomy Homo sapiens
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
C126102
Gene Ontology regulation of immune response to tumor cell
Human Disease Ontology cancer
NCIt Cancer Immunotherapy
occursIn
isDescribedBy

Curation status
Curated


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Model files

Leon-Triana2021 (eqs 1 and 2).xml SBML level 2 version 4 representation of the model 29.57 KB Preview | Download

Additional files

Fig 4b (tumour cells).png PNG file - Fig. 4(b) reproduction 9.79 KB Preview | Download
Leon-Triana2021 Fig 5a (tumour cells).png PNG file - Fig. 5(a) reproduction 118.71 KB Preview | Download
Fig 3b (tumour cells).png PNG file - Fig. 3(b) reproduction 11.85 KB Preview | Download
Leon-Triana2021 (eqs 1 and 2) - fig 5(a).sedml SEDML file - Fig. 5(a) simulation 2.81 KB Preview | Download
Leon-Triana2021 Fig 5a (CAR T-cells).png PNG file - Fig. 5(a) reproduction 109.74 KB Preview | Download
Fig 3b (CAR-T cells).png PNG file - Fig. 3(b) reproduction 13.00 KB Preview | Download
Leon-Triana2021 (eqs 1 and 2) - fig 4(c).sedml SEDML file - Fig. 4(c) simulation 5.12 KB Preview | Download
Leon-Triana2021 Fig 1a.png PNG file - Fig. 1(a) reproduction 128.88 KB Preview | Download
Fig 4b (CAR-T cells).png PNG file - Fig. 4(b) reproduction 11.31 KB Preview | Download
Leon-Triana2021 (eqs 1 and 2) - fig 3(a).sedml SEDML file - Fig. 3(a) simulation 5.14 KB Preview | Download
Leon-Triana2021 (eqs 1 and 2) - fig 4(b).sedml SEDML file - Fig. 4(b) simulation 5.12 KB Preview | Download
Leon-Triana2021 (eqs 1 and 2) - fig 1 (b, d).sedml SEDML file - Fig. 1(b, d) simulation 5.12 KB Preview | Download
Leon-Triana2021 Fig 1b.png PNG file - Fig. 1(b) reproduction 131.95 KB Preview | Download
Leon-Triana2021 Fig 1c.png PNG file - Fig. 1(c) reproduction 136.80 KB Preview | Download
Leon-Triana2021 (eqs 1 and 2) - fig 3(b).sedml SEDML file - Fig. 3(b) simulation 5.14 KB Preview | Download
Fig 4a (tumour cells).png PNG file - Fig. 4(a) reproduction 10.25 KB Preview | Download
Fig 3a (tumour cells).png PNG file - Fig. 3(a) reproduction 11.03 KB Preview | Download
Leon-Triana2021 (eqs 1 and 2) - fig 4(a).sedml SEDML file - Fig. 4(a) simulation 5.12 KB Preview | Download
Leon-Triana2021 Fig 1d.png PNG file - Fig. 1(d) reproduction 111.82 KB Preview | Download
Fig 4c (CAR-T cells).png PNG file - Fig. 4(c) reproduction 10.54 KB Preview | Download
Leon-Triana2021 (eqs 1 and 2).cps COPASI file 55.77 KB Preview | Download
Fig 4a (CAR-T cells).png PNG file - Fig. 4(a) reproduction 8.82 KB Preview | Download
Fig 3a (CAR-T cells).png PNG file - Fig. 3(a) reproduction 11.33 KB Preview | Download
Leon-Triana2021 (eqs 1 and 2) - fig 1 (a, c).sedml SEDML file - Fig. 1(a, c) simulation 5.12 KB Preview | Download
Fig 4c (tumour cells).png PNG file - Fig. 4(c) reproduction 9.38 KB Preview | Download

  • Model originally submitted by : Emilia Chen
  • Submitted: 12-Jul-2021 17:54:22
  • Last Modified: 23-Jul-2021 15:39:39
Revisions
  • Version: 6 public model Download this version
    • Submitted on: 23-Jul-2021 15:39:39
    • Submitted by: Emilia Chen
    • With comment: Automatically added model identifier BIOMD0000001013
  • Version: 4 public model Download this version
    • Submitted on: 13-Jul-2021 10:43:43
    • Submitted by: Emilia Chen
    • With comment: Automatically added model identifier BIOMD0000001013
  • Version: 2 public model Download this version
    • Submitted on: 12-Jul-2021 17:54:22
    • Submitted by: Emilia Chen
    • With comment: Automatically added model identifier BIOMD0000001013

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Curator's comment:
(added: 12 Jul 2021, 17:50:19, updated: 29 Jul 2021, 11:45:16)
Figure 5a of the reference manuscript representing the model in equations 1 and 2 was reproduced using COPASI 4.33.246. The value alpha_1 = 0.04 was used, instead of the value quoted in the manuscript caption for Figure 5.