Mathematical model of Chimeric Anti-gene Receptor (CAR) T cell therapy with presence of cytokine

Mostolizadeh, Reihaneh; Afsharnezhad, Zahra; Marciniak–Czochra, Anna

doi:10.3934/naco.2018004

Cited by 31 publications

(31 citation statements)

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“…Mathematical models have been developed to describe the complex interaction between the activated neutrophils/monocyte and pro inflammatory cytokines in bacteria‐induced sepsis, but none of these models can be used to investigate the CRS and CART cells in human subjects without major modifications . Recently, several mathematical models have been developed to describe the biologics of the CART . However, no clinical data are used to develop and validate these models, and, therefore, the ability of these models in describing the observed kinetics of cytokines and CART is questionable.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, several mathematical models have been developed to describe the biologics of the CART . However, no clinical data are used to develop and validate these models, and, therefore, the ability of these models in describing the observed kinetics of cytokines and CART is questionable.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, further investigation is needed to elucidate the quantitative relationship of CRS and the DB/CART dose in order to design an optimal dosing strategy for the prevention of the CRS. Recently, several mathematical models have been developed to provide theoretical speculation for the biologic of CART therapy, but none of these models has been used to describe the kinetic profiles of pro inflammatory cytokine and CART observed in patients with cancer treated with CART . Hence, in this study, we develop the first quantitative systems pharmacology (QSP) model that can describe the observed kinetic profiles of CART, DB, and pro inflammatory cytokines in a patient with advanced chronic lymphocytic leukemia (CLL) treated with anti‐CD19 CART therapy.…”

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confidence: 99%

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Quantitative Systems Pharmacology Model of Chimeric Antigen Receptor T‐Cell Therapy

Hardiansyah

2019

Clinical Translational Sci

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Chimeric antigen receptor T‐cell (CART) therapy is a new and promising cancer therapy. However, severe toxicity due to cytokine release syndrome (CRS) in CART‐treated patients highlighted the possible danger of this new therapy. Disease burden and CART doses are the potential factors associated with CRS but the detail relationships between these factors and the severity of the CRS remain largely unknown. In this study, the quantitative systems pharmacology (QSP) approach is used to quantify the complex relationships among CART doses, disease burden, and pro inflammatory cytokines in human subjects and to gain relevant insights into the determinant of clinical toxicity/efficacy in development of CART therapy. The expansion of CART and elimination of B cells are more highly correlated with disease burden than the administered CART doses. To our best knowledge, this is the first QSP model that can describe the observed clinical data from CART‐treated patients with cancer. This QSP model is a valuable tool for deepening our understanding of how the mechanism of action connects to the clinical outcomes and, therefore, may serve as an important model‐based platform to guide the development and personalized dosing of the CART therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Quantitative Systems Pharmacology Model of Chimeric Antigen Receptor T‐Cell Therapy

Hardiansyah

2019

Clinical Translational Sci

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“…The last term describes the decay of CAR T cells with a mean lifetime τ C . In contrast with previous modelling approaches [25,26,27], we exclude a death term in the CAR T cell compartment due to interaction with target cells. The reason is that CAR T cells do not undergo apoptosis after killing the target cell [28,29].…”

Section: Basic Mathematical Modelmentioning

confidence: 99%

CAR T cell therapy in B-cell acute lymphoblastic leukaemia: Insights from mathematical models

León-Triana¹,

Sabir

Calvo

et al. 2020

Preprint

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Immunotherapies use components of the patient immune system to selectively target cancer cells. The use of CAR T cells to treat B-cell malignanciesleukaemias and lymphomas-is one of the most successful examples, with many patients experiencing long-lasting complete responses to this therapy. This treatment works by extracting the patient's T cells and adding them the CAR group, which enables them to recognize and target cells carrying the antigen CD19 + , that is expressed in these haematological tumors.Here we put forward a mathematical model describing the time response of leukaemias to the injection of CAR T-cells. The model accounts for mature and progenitor B-cells, tumor cells, CAR T cells and side effects by incorporating the main biological processes involved. The model explains the early post-injection dynamics of the different compartments and the fact that the number of CAR T cells injected does not critically affect the treatment outcome. An explicit formula is found that provides the maximum CAR T cell 1 These two authors contributed equally to this work.

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“…In this work we aim to model mathematically the relationship between immunotherapy with CAR T cells and the long-term immunological memory. Some mathematical models have been recently developed representing tumor immune response to CAR T immunotherapy, either by assessing toxicity, interaction with other cells of the immune system, healthy cells, and tumor cells [1,49,38]. Just a few, however, have discussed the immunological memory in cancer [27,23].…”

Section: Introductionmentioning

confidence: 99%

Three-Compartment Model of CAR T-cell Immunotherapy

Rodrigues

Barros

Almeida

2019

Preprint

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Immunotherapy has gained great momentum with CAR T (chimeric antigen receptor) cellular therapy, in which the patient's T lymphocytes are genetically manipulated to recognize tumor-specific antigens to increase elimination efficiency. Although recently approved by FDA to treat B cell malignancies, issues such as dose, administration protocol, toxicity, resistance to immunotherapy, among others, remain open and are the subject of intense research nowadays. Improved CAR T cell immunotherapy requires a better understanding of the interplay between CAR T cell doses and tumor burden. We developed a threecompartment mathematical model to describe tumor response to CAR T cell immunotherapy in immunodeficient mouse models (NSG and SCID/beige) based on two published articles from literature. We modeled different receptors as CART 19BBz or CART 123, and different tumor targets as HDML-2 and RAJI. We considered interactions between tumor cells, effector T cells, and T cell differentiation into memory T cells; tumor-induced immunosuppressive effects, conversion of memory T cells into effector T cells in the presence of tumor cells, and individual specificities considered as uncertainties in the parameters of the model. The model was able to represent the two considered immunotherapy scenarios. For the HDML-2 scenario, the tumor is eliminated after the immunotherapy with the CAR T cells even in case of a challenge due to the memory T cells long-term immune protection. For the Raji tumor, expressing indoleamine 2,3-dioxygenase (IDO) activity, the model represented tumor dynamics even when IDO inhibitors are introduced. Using in silico studies considering different dosing quantities and tumor burden, we showed that the proposed model can represent the three possible outcomes: tumor elimination, equilibrium, and escape. We found that therapy effectiveness may also depend on small variations in the parameters' values, regarded as intrinsic individual specificities, as T cell proliferation capacity, as well as immunosuppressive tumor microenvironment factors. These issues may significantly reduce the chance of tumor elimination. In this way, the developed model provides potential use for assessing different CAR T cell protocols and associated efficacy without further in vivo experiments.

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Mathematical model of Chimeric Anti-gene Receptor (CAR) T cell therapy with presence of cytokine

Cited by 31 publications

References 0 publications

Quantitative Systems Pharmacology Model of Chimeric Antigen Receptor T‐Cell Therapy

Quantitative Systems Pharmacology Model of Chimeric Antigen Receptor T‐Cell Therapy

CAR T cell therapy in B-cell acute lymphoblastic leukaemia: Insights from mathematical models

Three-Compartment Model of CAR T-cell Immunotherapy

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