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BACKGROUND AND PURPOSE: Cotadutide is a dual GLP-1 and glucagon receptor agonist with balanced agonistic activity at each receptor designed to harness the advantages on promoting liver health, weight loss and glycaemic control. We characterised the effects of cotadutide on glucose, insulin, GLP-1, GIP, and glucagon over time in a quantitative manner using our glucose dynamics systems model (4GI systems model), in combination with clinical data from a multiple ascending dose/Phase 2a (MAD/Ph2a) study in overweight and obese subjects with a history of Type 2 diabetes mellitus (NCT02548585). EXPERIMENTAL APPROACH: The cotadutide PK-4GI systems model was calibrated to clinical data by re-estimating only food related parameters. In vivo cotadutide efficacy was scaled based on in vitro potency. The model was used to explore the effect of weight loss on insulin sensitivity and predict the relative contribution of the GLP-1 and glucagon receptor agonistic effects on glucose. KEY RESULTS: Cotadutide MAD/Ph2a clinical endpoints were successfully predicted. The 4GI model captured a positive effect of weight loss on insulin sensitivity and showed that the stimulating effect of glucagon on glucose production counteracts the GLP-1 receptor-mediated decrease in glucose, resulting in a plateau for glucose decrease around a 200-µg cotadutide dose. CONCLUSION AND IMPLICATIONS: The 4GI quantitative systems pharmacology model was able to predict the clinical effects of cotadutide on glucose, insulin, GLP-1, glucagon and GIP given known in vitro potency. The analyses demonstrated that the quantitative systems pharmacology model, and its successive refinements, will be a valuable tool to support the clinical development of cotadutide and related compounds.
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Glicemia , Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Modelos Biológicos , Receptores de Glucagon , Humanos , Receptores de Glucagon/agonistas , Receptores de Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipoglicemiantes/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Masculino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Controle Glicêmico , Pessoa de Meia-Idade , Feminino , Adulto , Glucagon/farmacologia , Glucagon/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Relação Dose-Resposta a Droga , PeptídeosRESUMO
Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) and dual GLP-1/glucagon receptor agonists improve glycaemic control and cause significant weight loss in patients with type 2 diabetes.1 These effects are driven in part by augmenting glucose-stimulated insulin release (incretin effect), reducing caloric intake and delayed gastric emptying. We developed and externally validated a novel integrated quantitative systems pharmacology (QSP) model to gain quantitative insight into the relative contributions and mechanisms of drugs modulating glucose regulatory pathways. This model (4GI model) incorporates known feedback mechanisms among glucose, GLP-1, glucagon, glucose-dependent insulinotropic peptide (GIP), and insulin after glucose provocation (i.e., food intake) and drug intervention utilizing published nonpharmacological and pharmacological (liraglutide, a GLP-1RA) data. The resulting model accurately describes the aforementioned mechanisms and independently predicts the effects of the GLP-1RAs (dulaglutide and semaglutide) on system dynamics. Therefore, the validated 4GI model represents a quantitative decision-making tool to support the advancement of novel therapeutics and combination strategies modulating these pathways.
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Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucose/metabolismo , Humanos , InsulinaRESUMO
Mathematical models in oncology aid in the design of drugs and understanding of their mechanisms of action by simulation of drug biodistribution, drug effects, and interaction between tumor and healthy cells. The traditional approach in pharmacometrics is to develop and validate ordinary differential equation models to quantify trends at the population level. In this approach, time-course of biological measurements is modeled continuously, assuming a homogenous population. Another approach, agent-based models, focuses on the behavior and fate of biological entities at the individual level, which subsequently could be summarized to reflect the population level. Heterogeneous cell populations and discrete events are simulated, and spatial distribution can be incorporated. In this tutorial, an agent-based model is presented and compared to an ordinary differential equation model for a tumor efficacy model inhibiting the pERK pathway. We highlight strengths, weaknesses, and opportunities of each approach.
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Modelos Teóricos , Neoplasias , Simulação por Computador , Humanos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Distribuição TecidualRESUMO
A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and functionally neutralizes interleukin-13. Thirty-two healthy male adults were enrolled into a dose-escalation clinical trial. Four active doses were tested (30, 105, 300, and 600 mg) with 6 volunteers enrolled per cohort. Eight volunteers received placebo as control. Following single subcutaneous administration (SC), individual time courses of serum MEDI7836 concentrations, and the resulting serum IL13 modulation in vivo, were quantified. A binding pharmacokinetic-pharmacodynamic (PK-PD) indirect response model was built to characterize the exposure-driven modulation of the target over time by MEDI7836. While the validated bioanalytical assay specification quantified the level of free target (i.e., a free IL13 assay), emerging clinical data suggested dose-dependent increase in systemic IL13 concentration over time, indicative of a total IL13 assay. The target time course was modelled as a linear combination of free target and a percentage of the drug-target complex to fit the clinical data. This novel PK-PD modelling approach integrates independent knowledge about the assay characteristics to successfully elucidate apparently complex observations.
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A 2-day meeting was held by members of the UK Quantitative Systems Pharmacology Network (
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Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos , Oncologia , Modelos Teóricos , Neoplasias Experimentais/tratamento farmacológico , Pesquisa Translacional Biomédica , Animais , Antineoplásicos/efeitos adversos , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Determinação de Ponto Final , Humanos , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Projetos de Pesquisa , Critérios de Avaliação de Resposta em Tumores Sólidos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Over the past decade, several immunotherapies have been approved for the treatment of melanoma. The most prominent of these are the immune checkpoint inhibitors, which are antibodies that block the inhibitory effects on the immune system by checkpoint receptors, such as CTLA-4, PD-1 and PD-L1. Preclinically, blocking these receptors has led to increased activation and proliferation of effector cells following stimulation and antigen recognition, and subsequently, more effective elimination of cancer cells. Translation from preclinical to clinical outcomes in solid tumors has shown the existence of a wide diversity of individual patient responses, linked to several patient-specific parameters. We developed a quantitative systems pharmacology (QSP) model that looks at the mentioned checkpoint blockade therapies administered as mono-, combo- and sequential therapies, to show how different combinations of specific patient parameters defined within physiological ranges distinguish different types of virtual patient responders to these therapies for melanoma. Further validation by fitting and subsequent simulations of virtual clinical trials mimicking actual patient trials demonstrated that the model can capture a wide variety of tumor dynamics that are observed in the clinic and can predict median clinical responses. Our aim here is to present a QSP model for combination immunotherapy specific to melanoma.
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Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Humanos , Imunoterapia/efeitos adversos , Melanoma/imunologia , Melanoma/patologia , Modelos Teóricos , Pacientes , Receptor de Morte Celular Programada 1/imunologiaRESUMO
The low response rate of immune checkpoint blockade in breast cancer has highlighted the need for predictive biomarkers to identify responders. While a number of clinical trials are ongoing, testing all possible combinations is not feasible. In this study, a quantitative systems pharmacology model is built to integrate immune-cancer cell interactions in patients with breast cancer, including central, peripheral, tumour-draining lymph node (TDLN) and tumour compartments. The model can describe the immune suppression and evasion in both TDLN and the tumour microenvironment due to checkpoint expression, and mimic the tumour response to checkpoint blockade therapy. We investigate the relationship between the tumour response to checkpoint blockade therapy and composite tumour burden, PD-L1 expression and antigen intensity, including their individual and combined effects on the immune system, using model-based simulations. The proposed model demonstrates the potential to make predictions of tumour response of individual patients given sufficient clinical measurements, and provides a platform that can be further adapted to other types of immunotherapy and their combination with molecular-targeted therapies. The patient predictions demonstrate how this systems pharmacology model can be used to individualize immunotherapy treatments. When appropriately validated, these approaches may contribute to optimization of breast cancer treatment.
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Immunotherapy and immune checkpoint blocking antibodies such as anti-PD-1 are approved and significantly improve the survival of advanced non-small cell lung cancer (NSCLC) patients, but there has been little success in identifying biomarkers capable of separating the responders from non-responders before the onset of the therapy. In this study, we developed a quantitative system pharmacology (QSP) model to represent the anti-tumor immune response in human NSCLC that integrated our knowledge of tumor growth, antigen processing and presentation, T cell activation and distribution, antibody pharmacokinetics, and immune checkpoint dynamics. The model was calibrated with the available data and was used to identify potential biomarkers as well as patient-specific response based on the patient parameters. The model predicted that in addition to tumor mutational burden (TMB), a known biomarker for anti-PD-1 therapy in NSCLC, the number of effector T cells and regulatory T cells in the tumor and blood is a predictor of the responders. Furthermore, the model simulated a set of 12 patients with known TMB and MHC/antigen-binding affinity from a recent clinical trial ( ClinicalTrials.gov number, NCT02259621) on neoadjuvant nivolumab therapy in resectable lung cancer and predicted an augmented durable response in patients with adjuvant nivolumab treatment in addition to the clinical trial protocol of neoadjuvant nivolumab treatment followed by resection. Overall, the model provides a valuable framework to model tumor immunity and response to immune checkpoint blockers to enhance biomarker discovery and performing virtual clinical trials to aid in design and interpretation of the current trials with fewer patients.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Modelos Biológicos , Nivolumabe/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos como Assunto , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Terapia Neoadjuvante , Nivolumabe/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Linear models are generally reliable methods for analyzing tumor growth in vivo, with drug effectiveness being represented by the steepness of the regression slope. With immunotherapy, however, not all tumor growth follows a linear pattern, even after log transformation. Tumor kinetics models are mechanistic models that describe tumor proliferation and tumor killing macroscopically, through a set of differential equations. In drug combination studies, although an additional drug-drug interaction term can be added to such models, however, the drug interactions suggested by tumor kinetics models cannot be translated directly into synergistic effects. We have developed a novel statistical approach that simultaneously models tumor growth in control, monotherapy, and combination therapy groups. This approach makes it possible to test for synergistic effects directly and to compare such effects among different studies.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imunoterapia/métodos , Modelos Teóricos , Neoplasias/tratamento farmacológico , Interações Medicamentosas , Sinergismo Farmacológico , Humanos , Cinética , Modelos Lineares , Neoplasias/patologia , Resultado do TratamentoRESUMO
Tremelimumab, an anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that enhances T-cell activation, was evaluated in a randomized, double-blind, placebo-controlled, phase IIb study (NCT01843374) in patients with unresectable malignant mesothelioma. The study demonstrated no clinically meaningful differences in overall survival (OS). The objective of this analysis was to evaluate the relationship of exposure with OS. A population pharmacokinetic (PK) model adequately described the PK data. Three factors (sex, C-reactive protein, and baseline tumor size) were identified as statistically significant PK predictors (P < 0.05 on clearance). A positive association between exposure and OS was observed. However, an association between key baseline factors with OS (regardless of treatment) and imbalances in prognostic factors favoring patients with higher exposure (upper vs. lower PK quartile) was seen. Taken together, these results suggest that the exposure OS relationship observed for tremelimumab in mesothelioma is likely spurious rather than a true association of exposure with efficacy.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacocinética , Fatores de Confusão Epidemiológicos , Humanos , Estimativa de Kaplan-Meier , Mesotelioma Maligno , Modelos Biológicos , Fatores de RiscoRESUMO
The lack of standardization in the way that quantitative and systems pharmacology (QSP) models are developed, tested, and documented hinders their reproducibility, reusability, and expansion or reduction to alternative contexts. This in turn undermines the potential impact of QSP in academic, industrial, and regulatory frameworks. This article presents a minimum set of recommendations from the UK Quantitative and Systems Pharmacology Network (UK QSP Network) to guide QSP practitioners seeking to maximize their impact, and stakeholders considering the use of QSP models in their environment.
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Hormônio Paratireóideo/farmacologia , Biologia de Sistemas/normas , Humanos , Modelos Biológicos , Hormônio Paratireóideo/efeitos adversos , Guias de Prática Clínica como Assunto , Reprodutibilidade dos Testes , Reino UnidoRESUMO
Precision medicine aims to use patient genomic, epigenomic, specific drug dose, and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State-of-the-art techniques to measure tumor drug penetration focus on systemic exposure, tissue penetration, cellular or molecular engagement, and expression of pharmacological activity. Using in silico methods, this information can be integrated to bridge the gap between the therapeutic regimen and the pharmacological link with clinical outcome. These methodologies are described, and challenges ahead are discussed. Supported by many examples, this review shows how the combination of these techniques provides enhanced patient-specific information on drug accessibility at the tumor tissue level, target binding, and downstream pharmacology. Our vision of how to apply tumor drug penetration measurements offers a roadmap for the clinical implementation of precision dosing.
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Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Medicina de Precisão/métodos , Absorção Fisiológica/genética , Absorção Fisiológica/fisiologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Ensaios Clínicos como Assunto , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Modelos Biológicos , Imagem Molecular/métodos , Neoplasias/genéticaRESUMO
Quantitative characterization of the tumor microenvironment, including its immuno-architecture, is important for developing quantitative diagnostic and predictive biomarkers, matching patients to the most appropriate treatments for precision medicine, and for providing quantitative data for building systems biology computational models able to predict tumor dynamics in the context of immune checkpoint blockade therapies. The intra- and inter-tumoral spatial heterogeneities are potentially key to the understanding of the dose-response relationships, but they also bring challenges to properly parameterizing and validating such models. In this study, we developed a workflow to detect CD8+ T cells from whole slide imaging data, and quantify the spatial heterogeneity using multiple metrics by applying spatial point pattern analysis and morphometric analysis. The results indicate a higher intra-tumoral heterogeneity compared with the heterogeneity across patients. By comparing the baseline metrics with PD-1 blockade treatment outcome, our results indicate that the number of high-density T cell clusters of both circular and elongated shapes are higher in patients who responded to the treatment. This methodology can be applied to quantitatively characterize the tumor microenvironment, including immuno-architecture, and its heterogeneity for different cancer types.
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Interleukin (IL)-13 is involved in the pathogenesis of some types of asthma. Tralokinumab is a human immunoglobulin G4 monoclonal antibody that specifically binds to IL-13. Two placebo-controlled phase II studies (phase IIa, NCT00873860 and phase IIb, NCT01402986) have been conducted in which tralokinumab was administered subcutaneously. This investigation aimed to characterize tralokinumab's dose-exposure-response (forced expiratory volume in 1 s (FEV1 )) relationship in patients with asthma and to predict the most appropriate dose for phase III. An integrated population pharmacokinetic-pharmacodynamic (PK/PD) modeling analysis was required for phase III dose selection, due to differing phase II patient populations, designs, and regimens. Analysis of combined datasets enabled the identification of tralokinumab's dose-exposure-FEV1 response relationship in patients with asthma. Near-maximal FEV1 increase was predicted at a dose of 300 mg SC once every 2 weeks (Q2W). This dose was chosen for tralokinumab in the phase III clinical development program for treatment of severe, uncontrolled asthma.
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Antiasmáticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Interleucina-13/antagonistas & inibidores , Adolescente , Adulto , Idoso , Asma/metabolismo , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, an anti-PD-L1 antibody, and quantify the impact of baseline and time-varying patient/disease characteristics on PK. Pooled data from two studies (1,409 patients providing 7,407 PK samples) were analyzed with nonlinear mixed effects modeling. Durvalumab PK was best described by a two-compartment model with both linear and nonlinear clearances. Three candidate models were evaluated: a time-invariant clearance (CL) model, an empirical time-varying CL model, and a semimechanistic time-varying CL model incorporating longitudinal covariates related to disease status (tumor shrinkage and albumin). The data supported a slight decrease in durvalumab clearance with time and suggested that it may be associated with a decrease in nonspecific protein catabolic rate among cancer patients who benefit from therapy. No covariates were clinically relevant, indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following weight-based and flat-dosing regimens.
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Anticorpos Monoclonais/farmacocinética , Cálculos da Dosagem de Medicamento , Taxa de Depuração Metabólica , Neoplasias/tratamento farmacológico , Antineoplásicos Imunológicos/farmacocinética , Antígeno B7-H1/imunologia , Simulação por Computador , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Estadiamento de Neoplasias , Neoplasias/classificação , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
Drug development is a lengthy, costly process with low probability of success. Biopharmaceuticals are highly specific molecules, with efficacy and safety closely tied to target biology and pharmacology. The "learning-predicting-confirming" continuum by translational and clinical modeling and simulation (M&S) was implemented at every decision point for mavrilimumab, a human monoclonal antibody in development for rheumatoid arthritis (RA). This tutorial uses mavrilimumab as an example to demonstrate rational discovery, preclinical development, clinical study design, and dose selection of biotherapeutics by M&S.
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Anticorpos Monoclonais/farmacologia , Produtos Biológicos/farmacologia , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Modelos Biológicos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Produtos Biológicos/efeitos adversos , Produtos Biológicos/farmacocinética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Valor Preditivo dos Testes , Estudo de Prova de Conceito , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacosRESUMO
The use of peptides as therapeutic agents is undergoing a renaissance with the expectation of new drugs with enhanced levels of efficacy and safety. Their clinical potential will be only fully realised once their physicochemical and pharmacokinetic properties have been precisely controlled. Here we demonstrate a reversible peptide self-assembly strategy to control and prolong the bioactivity of a native peptide hormone in vivo. We show that oxyntomodulin, a peptide with potential to treat obesity and diabetes, self-assembles into a stable nanofibril formulation which subsequently dissociates to release active peptide and produces a pharmacological effect in vivo. The subcutaneous administration of the nanofibrils in rats results in greatly prolonged exposure, with a constant oxyntomodulin bioactivity detectable in serum for at least 5 days as compared to free oxyntomodulin which is undetectable after only 4 h. Such an approach is simple, cost-efficient and generic in addressing the limitations of peptide therapeutics.
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Obesidade/tratamento farmacológico , Oxintomodulina/farmacocinética , Hormônios Peptídicos/farmacocinética , Animais , Glucose/metabolismo , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Oxintomodulina/administração & dosagem , Oxintomodulina/sangue , Oxintomodulina/química , Hormônios Peptídicos/administração & dosagem , Hormônios Peptídicos/sangue , Hormônios Peptídicos/química , Ratos , Ratos Sprague-DawleyRESUMO
When the immune system responds to tumour development, patterns of immune infiltrates emerge, highlighted by the expression of immune checkpoint-related molecules such as PDL1 on the surface of cancer cells. Such spatial heterogeneity carries information on intrinsic characteristics of the tumour lesion for individual patients, and thus is a potential source for biomarkers for anti-tumour therapeutics. We developed a systems biology multiscale agent-based model to capture the interactions between immune cells and cancer cells, and analysed the emergent global behaviour during tumour development and immunotherapy. Using this model, we are able to reproduce temporal dynamics of cytotoxic T cells and cancer cells during tumour progression, as well as three-dimensional spatial distributions of these cells. By varying the characteristics of the neoantigen profile of individual patients, such as mutational burden and antigen strength, a spectrum of pretreatment spatial patterns of PDL1 expression is generated in our simulations, resembling immuno-architectures obtained via immunohistochemistry from patient biopsies. By correlating these spatial characteristics with in silico treatment results using immune checkpoint inhibitors, the model provides a framework for use to predict treatment/biomarker combinations in different cancer types based on cancer-specific experimental data.