American Laboratory interviewed Aidan Synnott, Executive Director, Discovery Oncology, Charles River Laboratories, Wilmington, MA, U.S.A.
Q: What mouse models are used in modern cancer research?
A: There is a mixture of old and new in the models currently driving preclinical research. Among the older ones, human tumor xenografts in immunodeficient mice are still prevalent, and syngeneic murine models have seen a revival due to the advent of immuno-oncology. Among the newer ones, mice with an element of the human immune system (humanized models) are on the rise. There are also significant numbers of novel transgenic models in use, either as hosts for a grafted tumor or ones which result in spontaneous neoplasia.
Q: What is the role of these models in contemporary cancer studies, such as immuno-oncology?
A: Cell line xenografts remain a workhorse due to their extensive characterization and the large amount of historical data accumulated. Patient-derived xenografts provide more clinically relevant models, with the caveat that they are typically less well-characterized. Besides testing novel chemotherapies, inhibitors, and targeted therapies, both are useful in studying targets, potency, and side effects of cellular therapies, such as CAR-Ts [chimeric antigen receptor-T-cell], which are a recent innovation with great potential.
To study immunotherapies, syngeneic models are still the preferred tool due to their great degree of characterization and familiarity. The big drawback is that they require the target to be conserved between humans and mice, or else it is necessary to create a surrogate molecule. This is the case for the approved checkpoint PD-1 and CTLA-4 inhibitors. Humanized mice eliminate the need for cross-reactivity, but it will probably never be possible to reconstitute an entire native human immune system in a mouse. Thus, there are numerous subtypes of models available, depending on which subtype of the immune system the novel therapy is targeting (T-cells, B-cells, myeloid cells, natural killer cells, etc.).
Q: Are rodent models used in liquid biopsy development?
A: Rodent models are not useful in liquid biopsy development because most conventional murine cancer models do not spontaneously metastasize. There are some exceptions, but most liquid biopsy methods are developed directly from clinical samples.
Q: Are there other models of note/other research applications?
A: Immuno-oncology has spurred an increased demand for imaging in preclinical cancer assays. The advantage is that running tumor models orthotopically rather than subcutaneously allows a greater, more clinically relevant interaction with the immune system, particularly regarding tumor-infiltrating lymphocytes. The biggest interest is in bioluminescent or fluorescent imaging.
In addition, in vitro assays have been enhanced by the addition of improved technology such as high-content imaging. When applied to state-of-the-art in vitro assays such as 3-D tumor studies, this allows meaningful observation of the mechanism of action of biologics. There is a strong interest in assays where immune cells are co-cultured with tumor cells prior to research moving to the in vivo stage.
Q: What else does Charles River do in oncology research?
A: Charles River has expertise in the early discovery stage of oncology programs—from target identification through chemistry and screening. Combined with its extensive safety assessment capabilities and many industry veterans, it is well-placed to guide any company through the labyrinth by offering integrated drug discovery and development services.
For more information visit www.criver.com.