CRS Research Models

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CRS Research Models

Novel therapies such as chimeric antigen receptor T (CAR T) cell therapy, immuno-oncology therapy, and gene therapy have demonstrated efficacy in the treatment of various malignancies. However, the accompanying adverse events, the most common of which is cytokine release syndrome (CRS), substantially limit its wide application. To further study and to achieve better therapy of CRS, many different CRS models have been proposed to illustrate the occurrence and evolution of therapy-related CRS in specific disease. Creative Biolabs focuses on customized CRS research model development and provides customers with high-end customized solutions. On the basis of existing CRS models, Creative Biolabs provides in vitro or in vivo CRS research model development services for global clients, aiming at promoting your academic project.

Introduction

In CRS, cytokine levels show an obvious imbalance as inflammatory and anti-inflammatory cytokine compete with one another. This can cause various symptoms that range from some which are flu-like, to more serious conditions leading to organ failure or even death. Since multiple highly-interacting cytokines are involved in CRS, a good mathematical model is important to study the interaction of cytokines and guide the inhibition of single or multiple cytokines.

In Vitro CRS Model

In 2006, a Phase I clinical trial of TGN1412 caused a near-fatal cytokine storm reaction in 6 out of 6 healthy volunteers. Prior to the TGN1412 clinical trial disaster, the standard method for in vitro assessment of CRS was to add aqueous test antibody or biologic to a culture of PBMCs for 24h to 72h and then measure cell proliferation and inflammatory cytokine release. This simple approach is now recognized to lack sufficient sensitivity to accurately assess risk of CRS. Since then, a great deal of effort has gone into creating an in vitro assay that is capable of recapitulating in vivo effects. Three methods have been proposed to improve the ability to predict CRS:

Immobilization of test antibody on plastic
Co-culture of peripheral blood mononuclear cells (PBMCs) on HUVECs
Pre-culture of PBMCs at high cell density

Besides human PBMCs, nonhuman primate (NHP) model of CRS have also been developed by scientists. NHP PBMCs are essential models for a wide spectrum of biomedical research since they can often serve to link the translational research between small animal models and humans.

Modeling CRS after CAR-T cell transfer in mice reveals macrophages to be key players in CRS.

Fig.1 Modeling CRS after CAR-T cell transfer in mice reveals macrophages to be key players in CRS. (Rooney, 2018)

In Vivo CRS Models

PBMC-engrafted Humanized In Vivo Mouse Model

Encouraging new data indicates that many aspects of human CRS can be modeled in immunodeficient NSG mice engrafted with human PBMCs. Finding an appropriate mouse model is vital to understanding CRS and required for development of new treatments to enter into clinical trials. In a word, this model provides hope that new immuno-modulatory therapies can be safely developed and tested before clinical trials.

LPS-Induced Cytokine Release Model

For this kind of research model, animal (normally mouse) receives a lipopolysaccharide (LPS) injection. At specified time points post-LPS challenge, blood is collected for cytokine analysis. A rat intravenous (IV) LPS model has also been utilized to study different reference inhibitors to understand the pharmacology of the model. Creative Biolabs also offer the LPS-induced pulmonary neutrophilia model to investigate the effect of targeting mechanisms related to neutrophil recruitment and mediator release.

Donor-dependent In Vivo Mouse Model

Creative Biolabs has developed a series of rapid, sensitive and reproducible novels in vivo PBMC humanized mouse model that are able to differentiate human PBMC donors based on individual safety response to single agent and combination therapeutics of immune checkpoint inhibitors and possibly CAR-T therapy. This assay could be employed in future drug development.

At present, the pathobiology of severe CRS associated with some therapies has not been defined, and animal models are needed to derive mechanistic insights and test therapeutic interventions. If you are interested in CRS modeling, please feel free to contact us for more information.

Reference

Rooney, C.; Sauer, T. Modeling cytokine release syndrome. Nature medicine. 2018, 24(6): 705-706.