Mathematical modelling of the synergistic combination of radiotherapy and indoleamine-2,3-dioxygenase (IDO) inhibitory immunotherapy against glioblastoma

Chakwizira, Arthur; Ahlstedt, Jonatan; Redebrandt, Henrietta Nittby; Ceberg, Crister

doi:10.1259/bjr.20170857

Cited by 15 publications

(14 citation statements)

References 20 publications

(41 reference statements)

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“…Chakwizira et al. ( 22 ) simplified Serre’s original model to explain the immune response of radiation in combination with a checkpoint blocker targeting IDO, which is used in the context of treating glioblastoma. They only considered the short time immune response and replaced the complicated response after PD-1 checkpoint blocking in Serre’s model by a simplified dose response to IDO blockers.…”

Section: Model Approachesmentioning

confidence: 99%

Modeling Radioimmune Response—Current Status and Perspectives

2021

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The combination of immune therapy with radiation offers an exciting and promising treatment modality in cancer therapy. It has been hypothesized that radiation induces damage signals within the tumor, making it more detectable for the immune system. In combination with inhibiting immune checkpoints an effective anti-tumor immune response may be established. This inversion from tumor immune evasion raises numerous questions to be solved to support an effective clinical implementation: These include the optimum immune drug and radiation dose time courses, the amount of damage and associated doses required to stimulate an immune response, and the impact of lymphocyte status and dynamics. Biophysical modeling can offer unique insights, providing quantitative information addressing these factors and highlighting mechanisms of action. In this work we review the existing modeling approaches of combined ‘radioimmune’ response, as well as associated fields of study. We propose modeling attempts that appear relevant for an effective and predictive model. We emphasize the importance of the time course of drug and dose delivery in view to the time course of the triggered biological processes. Special attention is also paid to the dose distribution to circulating blood lymphocytes and the effect this has on immune competence.

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Section: Model Approachesmentioning

confidence: 99%

Modeling Radioimmune Response—Current Status and Perspectives

2021

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“…To further analyze the effect of the fractionation interval, a mathematical tumor growth model described in a previous paper [26] was fitted to the tumor size measurements on day 18. In brief, the model accounts for the radiation-triggered recruitment and activation of immune effector cells, in synergy with the inhibitory effect of 1-MT on the tumor's immuno-suppressive properties.…”

Section: Fractionation Studymentioning

confidence: 99%

“…In this work, the exponential tumor growth function of the original model was PLOS ONE replaced by a Gompertz function, as this was subsequently found to better represent the intracranial growth of the present rat glioma model [30]. The model parameters were found by using the least square method with the lsqnonlin function in Matlab, whereas initial value estimates were obtained from our previous reports [26]. In order to estimate the uncertainty of the model, the fit was repeated 10,000 times with the data for each experimental treatment group resampled using bootstrapping with replacement.…”

Section: Fractionation Studymentioning

confidence: 99%

“…For the untreated controls, immunotherapy-only, and radiotherapy-only groups, the median survival time was 20±0.99 days, 18 ±0.28 days and 17±2.74 days respectively. We have applied a mathematical model developed by Serre et al [25] to describe the combined effect of radiotherapy and immunotherapy [26]. Extrapolating from this provided that, in a two-fraction irradiation scheme, the synergy may be improved by short fraction intervals of 2-3 days, and that it decreased with increasing intervals.…”

Section: Introductionmentioning

confidence: 99%

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Increased effect of two-fraction radiotherapy in conjunction with IDO1 inhibition in experimental glioblastoma

et al. 2020

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The aim of the study was to investigate therapeutic efficacy of single-or two-fraction radiotherapy in conjunction with IDO1-inhibition in a syngeneic rat glioblastoma model. IDO is known to cause immunosuppression through breakdown of tryptophan in the tumor microenvironment. MethodsGene expression analyses of IDO in glioblastoma were performed with data from publicly available datasets. Fractionation studies were done on animals to evaluate tumor size, immune cell infiltration of tumors and serum profile on day 18 after tumor inoculation. Survival analyses were done with animals carrying intracranial glioblastomas comparing twofraction radiotherapy+IDO1-inhibition to controls. IDO inhibition was achieved by administration of 1-methyl tryptophan (1-MT), and radiotherapy (RT) was delivered in doses of 8Gy. ResultsThe expression of IDO1 was increased on gene level in glioblastoma stem cells. Tumor size was significantly reduced in animals treated with 1-MT+RTx 2 (both long and short intervals, i.e. 7 and 4 days between the treatments) as compared to control animals, animals treated with only 1-MT or animals treated with 1-MT+RTx1. Serum levels of IL-1A were significantly altered in all treated animals as compared to control animals. Survival was significantly increased in the animals treated with 1-MT+RTx2 (7-day interval) compared to control animals. ConclusionsAddition of two-fraction RT to IDO1 inhibition with 1-MT significantly reduced tumor size in animals with glioblastoma. Survival was significantly increased in animals treated with twofractioned RT+1-MT as compared to untreated controls increased significantly.

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“…Studies of radiotherapy can also use discrete-time dynamical systems or difference equations for tumor growth. A recent study by Chakwizira et al used difference equations for the synergistic combination of radiotherapy and immunotherapy [21]. Some hybrid multiscale mathematical models for radiotherapy have been also proposed.…”

Section: Introductionmentioning

confidence: 99%

Modeling of tumor radiotherapy with damage and repair processes

Zhao¹,

Wei²,

Tian³

2021

Preprint

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Background: Under irradiation, some cells are damaged permanently and die while some damaged cells can be self-repaired and become normal cells. The same situation happens in tumor radiotherapy. There has been several models to calculate the probability of cell survival after irradiation, and mathematical models for tumor growth to incorporate cell survival probability in radiotherapy. However, there is no detailed study about how both radiation damage process and cell repair process impact outcomes of tumor radiotherapy. This study will focus on impacts of these two processes on tumor radiotherapy. Methods: The study employs mathematical modeling. Based on established mathematical models for tumor growth and irradiation, a functional reaction diffusion system for tumor radiotherapy is proposed. The model has the tumor cell population and damaged tumor cell population, and tracks their movements in the tumor site. The model considers the repair time of damaged tumor cells as a delay parameter. Detailed analysis is conducted while numerical simulations are performed with glioma data. Results: We obtain the radiation threshold which combines the tumor growth rate, the damaged cell death rate, and damaged cell repair rate. The radiation threshold is a decreasing function of radiation dose while the radiation damage rate is a increasing function of radiation dose. The radiation damage rate and repair time determine the outcome of radiotherapy. When the radiation damage rate is greater than the radiation threshold, radiotherapy may destroy the tumor while radiotherapy may control tumor growth and the tumor load decreases as the radiation dose increases when the radiation damage rate is less than the radiation threshold. For both situations, we also observe oscillations of two cell populations occurring from Hopf bifurcations and Turing instability appearing from a large repair time of damaged tumor cells and different cell motilities. Conclusions: The damaged tumor cell repairing process increases the radiation threshold and complicates outcomes of radiotherapy. The medical implication of our results is that radiotherapy may control the tumor growth and the radiation dose can reduce the total tumor load when the damage rate is greater than the radiation threshold, and otherwise, radiotherapy may kill the tumor and the amount of the does not matter.

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Mathematical modelling of the synergistic combination of radiotherapy and indoleamine-2,3-dioxygenase (IDO) inhibitory immunotherapy against glioblastoma

Cited by 15 publications

References 20 publications

Modeling Radioimmune Response—Current Status and Perspectives

Modeling Radioimmune Response—Current Status and Perspectives

Increased effect of two-fraction radiotherapy in conjunction with IDO1 inhibition in experimental glioblastoma

Modeling of tumor radiotherapy with damage and repair processes

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