An interview with Dr. Julia Schueler, Research Director at Charles River Laboratories (Part 2)
What are the limitations of current in vivo models for IO development?
Syngeneic mouse models cover the complete spectrum of immune cells to be activated but have the downside of requiring a mouse surrogate, which have key biological differences to a human immune system, such as differences in B cell markers, B cell development and of course many other differences we haven’t discovered yet. In addition, there is also a limited number of tumour lines (<30) available so you cannot do a wide screen using syngeneic mouse models.
Humanized mice have the advantage of offering >1000 models (cell lines and PDX) but, at least at the moment, they are limited to only being able to model T-cell related therapies as B cells and NK cells are heavily underrepresented in these models. Next generation humanised mouse models (NSG 1/3) express more cytokines and the myeloid compartment is represented much better but they are also more fragile, very expensive and not a good option for long-term dosing.
GEMMs are another option but they are only engineered to produce one specific tumour type – not the 40 types of NSCLC for you to screen against as an example, so it’s not possible to test the complete tumour population that you would see represented in patients.
What new preclinical models/testing approaches are on the horizon?
- In vitro: Optimising matrices to be able to grow all sorts of different cell types to better reflect the tumour biology and make handling 3D cultures more manageable.
- In vivo: Development of new mouse strains that enable the engraftment of immune cells other than T cells.
What potential do organoids hold for IO modelling?
It’s important to get the definition of an organoid right as it’s often not used correctly – an organoid is something grown from an epithelial stem cell in a matrix, which self-assembles into a mini organ-like structure. We cannot currently combine organoids with immune cells. However, we can do 3D studies using immune cells co-cultured with tumour cells – this is what is known as a spheroid (but can also be called a variety of names, such as tumoroids etc.).
New therapies coming that will have a big impact on cancer treatment
I’m biased as my research is focused on small molecules, but small molecules are stable, easy to produce, we generally know more about them, and they can be administered orally. In addition to small molecules, I think more cell-based therapies, such as CAR-T cells and CAR-NK cells, as well as other new modalities are looking very promising.
Interested in the progress made to develop more physiologically representative syngeneic mouse models for immuno-oncology modelling?
Download our whitepaper for a comprehensive review of syngeneic mouse models currently available and their limitations.
Image credit: sourced from Shuttershock