Pharmacokinetic enhancement of oncolytic virus M1 by inhibiting JAK‒STAT pathway

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(6), P. 2554 - 2566

Published: March 11, 2024

Oncolytic viruses (OVs), a group of replication-competent that can selectively infect and kill cancer cells while leaving healthy intact, are emerging as promising living anticancer agents. Unlike traditional drugs composed non-replicating compounds or biomolecules, the replicative nature confer unique pharmacokinetic properties require further studies. Despite some pharmacokinetics studies OVs, mechanistic insights into connection between OV antitumor efficacy remain vague. Here, we characterized profile oncolytic virus M1 (OVM) in immunocompetent mouse tumor models identified JAK‒STAT pathway key modulator OVM pharmacokinetics. By suppressing pathway, early ameliorated, leading to enhanced tumor-specific viral accumulation, increased AUC Cmax, improved efficacy. Rather than compromising immunity after inhibition, promotes T cell recruitment activation microenvironment, providing an optimal opportunity for therapeutic outcome immune checkpoint blockade, such anti-PD-L1. Taken together, this study advances our understanding pharmacokinetic-pharmacodynamic relationship therapy.

Language: Английский

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Threshold dynamics of a stochastic tumor-immune model combined oncolytic virus and chimeric antigen receptor T cell therapies

Chaos Solitons & Fractals, Journal Year: 2025, Volume and Issue: 197, P. 116418 - 116418

Published: April 25, 2025

Language: Английский

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A combination therapy of oncolytic viruses and chimeric antigen receptor T cells: a mathematical model proof-of-concept

Mathematical Biosciences & Engineering, Journal Year: 2022, Volume and Issue: 19(5), P. 4429 - 4457

Published: Jan. 1, 2022

Combining chimeric antigen receptor T (CAR-T) cells with oncolytic viruses (OVs) has recently emerged as a promising treatment approach in preclinical studies that aim to alleviate some of the barriers faced by CAR-T cell therapy. In this study, we address means mathematical modeling main question whether single dose or multiple sequential doses during OVs therapy can have synergetic effect on tumor reduction. To end, propose an ordinary differential equations-based model virus-induced synergism investigate potential effects different regimes could result efficacious combination against populations. Model simulations show that, while is inadequate eliminate all cells, combining same successfully absence synergism. However, presence synergism, fails tumor. Furthermore, it shown if intensity synergy and/or virus potency high, then induced response inhibit oncolysis. Additionally, more robust synergistic reduction when and are administered simultaneously compared where first after OV injection. Our findings suggest seems unlikely be effective included genetically engineering viral vectors.

Language: Английский

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Assessment of Clinical Response to V937 Oncolytic Virus After Intravenous or Intratumoral Administration Using Physiologically‐Based Modeling

Clinical Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 114(3), P. 623 - 632

Published: May 12, 2023

Oncolytic viruses (OVs) represent a potential therapeutic strategy in cancer treatment. However, there is currently lack of comprehensive quantitative models characterizing clinical OV kinetics and distribution to the tumor. In this work, we present mechanistic modeling framework for V937 OV, after intratumoral (i.t.) or intravascular (i.v.) administration patients with cancer. A minimal physiologically-based pharmacokinetic model was built characterize biodistribution OVs humans. Viral dynamics incorporated at i.t. cellular level linked tumor response, enabling characterization direct killing triggered by death infected cells an indirect induced immune response. The provided adequate description changes mRNA levels size obtained from phase I/II trials administration. showed prominent role viral clearance systemic circulation infectivity addition known aggressiveness on After i.v. administration, exposure predicted be several orders magnitude lower compared These differences could overcome if high virus and/or replication. Unfortunately, latter process not identified current setting. This work provides insights selecting optimal considering replication rate infectivity.

Language: Английский

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Optimal strategies of oncolytic virus-bortezomib therapy via the apoptotic, necroptotic, and oncolysis signaling network

Mathematical Biosciences & Engineering, Journal Year: 2024, Volume and Issue: 21(3), P. 3876 - 3909

Published: Jan. 1, 2024

<abstract><p>Bortezomib and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts protein degradation in cells, leading to the accumulation of unfolded proteins that induce apoptosis. On other hand, uses genetically modified viruses (OVs) infect trigger cell lysis, activate anti-tumor response. Despite progress treatment, identifying administration protocols for therapeutic agents remains significant concern, aiming strike balance between efficacy, minimizing toxicity, administrative costs. In this work, optimal control theory was employed design cost-effective efficient co-administration bortezomib OVs could significantly diminish population cells via death program with NF$ \kappa $B-BAX-RIP1 signaling network. Both linear quadratic strategies were explored obtain practical treatment approaches by adapting necroptosis programs. Our findings demonstrated combination therapy commencing followed infusions yields an effective tumor-killing outcome. These results provide valuable guidance development clinical treatment.</p></abstract>

Language: Английский

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Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral replication

Molecular Therapy — Methods & Clinical Development, Journal Year: 2022, Volume and Issue: 28, P. 190 - 207

Published: Dec. 28, 2022

Viral replication places oncolytic viruses (OVs) in a unique niche the field of drug pharmacokinetics (PK) as their self-amplification obscures exposure-response relationships. Moreover, standard bioanalytical techniques are unable to distinguish input from replicated products. Here, we combine two novel approaches characterize PK and biodistribution (BD) after systemic administration vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis glycoprotein (VSV-GP) healthy mice. First: decouple PK/BD versus PK/BD, developed fully characterized replication-incompetent tool that retained all other critical attributes drug. We used this approach quantify blood tissues determine its impact on BD. Second: discriminate genomic antigenomic viral RNA strands contributing dynamics tissues, an situ hybridization method using strand-specific probes assessed spatiotemporal distribution tissues. This latter demonstrated distribution, transcription, localized tissue-resident macrophages, indicating role Ultimately, our study results refined profile for replicating OV, new proposed parameters, deeper understanding OV could be applied vectors.

Language: Английский

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Mathematical Modeling of Oncolytic Virus Therapy Reveals Role of the Immune Response

Viruses, Journal Year: 2023, Volume and Issue: 15(9), P. 1812 - 1812

Published: Aug. 25, 2023

Oncolytic adenoviruses (OAds) present a promising path for cancer treatment due to their selectivity in infecting and lysing tumor cells ability stimulate the immune response. In this study, we use an ordinary differential equation (ODE) model of growth inhibited by oncolytic virus activity parameterize previous research on effect genetically re-engineered OAds A549 lung tumors murine models. We find that data are best fit accounts response, response provides mechanism elimination tumor. also parameter estimates most effective share characteristics, notably high infection rate low viral clearance rate, might be potential reasons these viruses’ efficacy delaying growth. Further studies observing E1A P19 recombined viruses different environments may further illuminate extent effects genetic modifications.

Language: Английский

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Prospective approaches to gene therapy computational modeling – spotlight on viral gene therapy

Journal of Pharmacokinetics and Pharmacodynamics, Journal Year: 2023, Volume and Issue: 51(5), P. 399 - 416

Published: Oct. 17, 2023

Abstract Clinical studies have found there still exists a lack of gene therapy dose-toxicity and dose-efficacy data that causes dose selection to remain elusive. Model informed drug development (MIDD) has become standard tool implemented throughout the discovery, development, approval pharmaceutical therapies, potential inform relationships support selection. Despite this potential, MIDD approaches for immature require standardization be useful clinical programs. With goal advance therapy, in review we first provide an overview types how they differ from bioanalytical, formulation, route administration, regulatory standpoint. biological background, propose can advanced AAV-based therapies by utilizing physiological based pharmacokinetic modeling quantitative systems pharmacology holistically AAV target protein dynamics following dosing. We discuss proposed model, allowing in-depth exploration pharmacology, could key field needs treat these unmet disease populations.

Language: Английский

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A Light sheet fluorescence microscopy and machine learning-based approach to investigate drug and biomarker distribution in whole organs and tumors

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 17, 2023

Abstract Tissue clearing and Light sheet fluorescence microscopy (LSFM) provide spatial information at a subcellular resolution in intact organs tumors which is significant advance over tools that limit imaging to few representative tissue sections. The distribution of drugs, targets, biomarkers can help inform relationships between exposure the site action, efficacy, safety during drug discovery. We demonstrate use LSFM investigate an oncolytic virus (OV) vasculature xenograft tumors, as well brain Aβ pathology Alzheimer’s disease (AD) mouse model. Machine learning-based image analysis developed segment showed random forest deep learning methods provided superior segmentation accuracy vs intensity-based thresholding. Sub-cellular enabled detection punctate diffuse intracellular OV profiles. investigation TgCRND8 AD model 6.5 months age evaluation plaque density different regions. utility data support quantitative systems pharmacology (QSP) physiology-based pharmacokinetics (PBPK) modeling development are also discussed. In summary, we showcase how expand our understanding macromolecular biomarker discovery development.

Language: Английский

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Disentangling Anti‐Tumor Response of Immunotherapy Combinations: A Physiologically Based Framework for V937 Oncolytic Virus and Pembrolizumab

Clinical Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: unknown

Published: July 22, 2024

Immuno‐oncology (IO) is a growing strategy in cancer treatment. Oncolytic viruses (OVs) can selectively infect cells and lead to direct and/or immune‐dependent tumor lysis. This approach represents an opportunity potentiate the efficacy of immune checkpoint inhibitors (ICI), such as pembrolizumab. Currently, there lack comprehensive quantitative models for aforementioned scenarios. In this work, we developed mechanistic framework describing viral kinetics, dynamics, response after intratumoral (i.t.) or intravenous (i.v.) administration V937 alone combination with The model accounts shrinkage, both injected non‐injected lesions, induced by: viral‐infected cell death activated CD8 cells. OV‐infected enhanced expansion cells, whereas pembrolizumab inhibits their exhaustion by competing PD‐L1 binding PD‐1. Circulating levels treatment effects on volume were adequately characterized all different mechanistic‐based has been combining top‐down bottom‐up approaches provides individual estimates ICI responses. robustness reflected description size time profiles variety clinical Additionally, platform allows us investigate not only contribution processes related kinetics dynamics response, but also influence its interaction ICI. be used explore scenarios aiming optimize combinations support development.

Language: Английский

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