Cancer Models Forum

Posted by Repositive, October 2020

How to select a model for the preclinical development of your immunotherapy

An interview with Dr. Julia Schueler, Research Director at Charles River Laboratories (Part 1)

Could you give an overview of the preclinical development process for an immunotherapy?

In principal, the preclinical development process is very similar for both immunotherapies and non-IO therapies, in the sense that the steps required are the same - target ID, hit to lead, in vitro HTS, in vivo toxicology screening, IND filing etc. For both IO and non-IO therapies, you need to show significant evidence of efficacy and safety, so the large scientific question behind the preclinical development of each is similar but the platforms used are different. There are however differences when looking at an antibody, small molecule or cell therapy.

Are there regulatory requirements as to which models need to be used for IO vs. non-IO therapies?

There aren’t any specific models or assays that are required to be used in the preclinical development of an IO therapy – however, as I mentioned, you need to be able to show significant evidence of efficacy and safety to satisfy regulatory requirements.

What are the main in vitro and in vivo assays and model types used for IO studies?

The platforms for the different steps of the drug development process have to reflect the fact that either the target cells are not tumour cells (CPi), that the compound is a cell itself (CAR T-cells) or that the compound is only active against the tumour cell when another cell type (immune cells) is present. For non-IO compounds, you need to consider how best to model the tumour cells; however, for IO compounds, at least one other cell type (an immune cell type) has to be reflected in your model.

  • In vitro assays – IO assays are mostly very T-cell focused at the moment, where a T-cell is placed in context with tumour cells to model the interaction you want to test; for example, T-cell killing assays in 2D and 3D.

  • In vivo models – The main platforms for in vivo IO modelling currently are syngeneic mouse models and models using humanized mice (immune compromised mice injected with human immune cells from different sources).

Could you give an overview of the key factors that need to be considered when selecting an IO model or assay?

This is very similar to the assays in a non-IO field: the platform has to be able to test the modality – for example, the presence of target cells, media composition to fit the CAR T-cells, matrix composition to enable the activation of the compound etc. The platform has to be robust and to a certain extent capable of high-throughput screening.

What are some of the key limitations with the in vitro IO assays currently available?

Currently, no platform is able to cover all scientific questions. That being said, the more complex the platform is, the less is the likelihood of it being compatible with high-throughput screening. In addition, price and timelines increase and robustness drops.

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