Integration of the Immune System into Complex In Vitro Models for Preclinical Drug Development

AbstractInvestigational in vitro models that reflect the complexity of the interaction between the immune system and tumours are limited and difficult to establish. Herein, we present a platform to study the tumour-immune interaction using a co-culture between cancer spheroids and activated immune cells. An algorithm was developed for analysis of confocal images of the co-culture to evaluate the following quantitatively; immune cell infiltration, spheroid roundness and spheroid growth. As a proof of concept, the effect of the glucocorticoid stress hormone, cortisol was tested on 66CL4 co-culture model. Results were comparable to 66CL4 syngeneic in vivo mouse model undergoing psychological stress. Furthermore, administration of glucocorticoid receptor antagonists demonstrated the use of this model to determine the effect of treatments on the immune-tumour interplay. In conclusion, we provide a method of quantifying the interaction between the immune system and cancer, which can become a screening tool in immunotherapy design.

Download Full-text

Designing Human In Vitro Models for Drug Development

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2019.12.013 ◽

2020 ◽

Vol 75 (6) ◽

pp. 587-589

Author(s):

Richard C. Becker ◽

Sakthivel Sadayappan

Keyword(s):

Drug Development ◽

In Vitro Models

Download Full-text

Characterization and applications of chimeric mice with humanized livers for preclinical drug development

Laboratory Animal Research ◽

10.1186/s42826-019-0032-y ◽

2020 ◽

Vol 36 (1) ◽

Cited By ~ 4

Author(s):

Chise Tateno ◽

Yuha Kojima

Keyword(s):

Liver Function ◽

Drug Development ◽

Mass Production ◽

Human Hepatocytes ◽

In Vitro Studies ◽

New Drugs ◽

Pharmaceutical Companies ◽

Chimeric Mice ◽

Preclinical Drug Development

AbstractWe have succeeded in stable mass production of chimeric PXB-mice, whose liver is repopulated by human hepatocytes at a ratio of more than 70%, and we are providing these mice to academia and pharmaceutical companies to support the development of new drugs or studies of liver function. Furthermore, we isolated human hepatocytes, called PXB-cells, from the chimeric mice, and provide them for clients weekly for in vitro studies. In this review, we summarize the existing characterizations of PXB-mice and PXB-cells and their present and future applications.

Download Full-text

From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights

Biomedicines ◽

10.3390/biomedicines10010161 ◽

2022 ◽

Vol 10 (1) ◽

pp. 161

Author(s):

Alexandra Gatzios ◽

Matthias Rombaut ◽

Karolien Buyl ◽

Joery De Kock ◽

Robim M. Rodrigues ◽

...

Keyword(s):

Liver Disease ◽

Drug Development ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Drug Testing ◽

Disease Modeling ◽

In Vitro Models ◽

Alcoholic Fatty Liver ◽

Short Term Exposure

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs.

Download Full-text

Mesenchymal Stem Cells in COVID-19: A Journey from Bench to Bedside

Laboratory Medicine ◽

10.1093/labmed/lmaa049 ◽

2020 ◽

Vol 52 (1) ◽

pp. 24-35

Author(s):

Kamal Kant Sahu ◽

Ahmad Daniyal Siddiqui ◽

Jan Cerny

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Immune System ◽

Therapeutic Option ◽

Antiviral Agent ◽

In Vitro Models ◽

Human Immune System ◽

Economic Sectors ◽

Human Immune

Abstract The COVID-19 pandemic has led to a major setback in both the health and economic sectors across the globe. The scale of the problem is enormous because we still do not have any specific anti-SARS-CoV-2 antiviral agent or vaccine. The human immune system has never been exposed to this novel virus, so the viral interactions with the human immune system are completely naive. New approaches are being studied at various levels, including animal in vitro models and human-based studies, to contain the COVID-19 pandemic as soon as possible. Many drugs are being tested for repurposing, but so far only remdesivir has shown some positive benefits based on preliminary reports, but these results also need further confirmation via ongoing trials. Otherwise, no other agents have shown an impactful response against COVID-19. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease.

Download Full-text

Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development

International Journal of Molecular Sciences ◽

10.3390/ijms221910254 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10254

Author(s):

Johanna Heider ◽

Sabrina Vogel ◽

Hansjürgen Volkmer ◽

Ricarda Breitmeyer

Keyword(s):

Drug Development ◽

Neuropsychiatric Disorders ◽

Autism Spectrum ◽

In Vitro Models ◽

Neuropsychiatric Diseases ◽

Culture Models ◽

Target Screening ◽

Induced Pluripotent ◽

The Impact

Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development.

Download Full-text

Targeting Cellular DNA Damage Responses in Cancer: An In Vitro-Calibrated Agent-Based Model Simulating Monolayer and Spheroid Treatment Responses to ATR-Inhibiting Drugs

Bulletin of Mathematical Biology ◽

10.1007/s11538-021-00935-y ◽

2021 ◽

Vol 83 (10) ◽

Author(s):

Sara Hamis ◽

James Yates ◽

Mark A. J. Chaplain ◽

Gibin G. Powathil

Keyword(s):

Dna Damage ◽

Drug Development ◽

Agent Based Model ◽

Agent Based ◽

Preclinical Drug Development ◽

Dna Damage Responses ◽

Treatment Responses ◽

Cellular Dna

AbstractWe combine a systems pharmacology approach with an agent-based modelling approach to simulate LoVo cells subjected to AZD6738, an ATR (ataxia–telangiectasia-mutated and rad3-related kinase) inhibiting anti-cancer drug that can hinder tumour proliferation by targeting cellular DNA damage responses. The agent-based model used in this study is governed by a set of empirically observable rules. By adjusting only the rules when moving between monolayer and multi-cellular tumour spheroid simulations, whilst keeping the fundamental mathematical model and parameters intact, the agent-based model is first parameterised by monolayer in vitro data and is thereafter used to simulate treatment responses in in vitro tumour spheroids subjected to dynamic drug delivery. Spheroid simulations are subsequently compared to in vivo data from xenografts in mice. The spheroid simulations are able to capture the dynamics of in vivo tumour growth and regression for approximately 8 days post-tumour injection. Translating quantitative information between in vitro and in vivo research remains a scientifically and financially challenging step in preclinical drug development processes. However, well-developed in silico tools can be used to facilitate this in vitro to in vivo translation, and in this article, we exemplify how data-driven, agent-based models can be used to bridge the gap between in vitro and in vivo research. We further highlight how agent-based models, that are currently underutilised in pharmaceutical contexts, can be used in preclinical drug development.

Download Full-text

In Vitro Immune Organs-on-Chip for Drug Development: A Review

Pharmaceutics ◽

10.3390/pharmaceutics10040278 ◽

2018 ◽

Vol 10 (4) ◽

pp. 278 ◽

Cited By ~ 16

Author(s):

Aya Shanti ◽

Jeremy Teo ◽

Cesare Stefanini

Keyword(s):

Immune System ◽

Drug Development ◽

Attrition Rate ◽

Human Immune System ◽

Drug Candidates ◽

Immune Organs ◽

On Chip ◽

High Attrition Rate

The current drug development practice lacks reliable and sensitive techniques to evaluate the immunotoxicity of drug candidates, i.e., their effect on the human immune system. This, in part, has resulted in a high attrition rate for novel drugs candidates. Organ-on-chip devices have emerged as key tools that permit the study of human physiology in controlled in vivo simulating environments. Furthermore, there has been a growing interest in developing the so called “body-on-chip” devices to better predict the systemic effects of drug candidates. This review describes existing biomimetic immune organs-on-chip, highlights their physiological relevance to drug development and discovery and emphasizes the need for developing comprehensive immune system-on-chip models. Such immune models can enhance the performance of novel drug candidates during clinical trials and contribute to reducing the high attrition rate as well as the high cost associated with drug development.

Download Full-text