Advanced Oncology Treatment Candidates Developed With Next-Generation Preclinical Models
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Despite the significant progress made in oncology drug development over the last few decades, developers still face substantial challenges in delivering efficacious treatments. Most notably, in many cancers, there are complex interactions between the tumor microenvironment (TME) and immune system cells that are not fully understood, making it difficult for researchers to develop drugs that account for this relationship. As a result, drug development is long, expensive and rarely successful.
One factor that can significantly impact the success of oncology drug development is the preclinical model used. The right model can provide valuable insights into key interactions within the body and help researchers to better understand how tumors respond to treatment. Deeper understanding of complex interactions leads to better-designed drugs with an improved likelihood of efficacy in clinical studies. Yet nearly 90% of novel drugs that pass preclinical tests are failing during human trials1 — why?
In this article, we explore the role of preclinical models in oncology drug discovery and how the right model can help to accelerate the development of the most promising treatments.
Finding the right preclinical model
Of all the preclinical models available to use during drug development, most researchers opt for mouse models. There are several factors that contribute to the attractiveness of mouse models, most notably that they are biologically similar to humans and can be easily genetically manipulated to mimic human conditions. Further securing their popularity is their accelerated lifespan, which allows for the rapid study of the whole lifecycle. What’s more, mice are economical and easy to breed, making them a cost-effective choice for preclinical research.
However, not all mouse models are equal, and some have drawbacks that must be considered. Crucially, not every model fully recapitulates the human immune system, making it difficult to determine all the relevant interactions between immune cells and the TME. This can lead to missed key interactions that affect treatment efficacy, such as dosages, pharmacokinetic and pharmacodynamic data. Furthermore, only T cells remain after a few days in some models, leading to the loss of monocyte dendritic cells (DCs) and an increased risk of graft versus host disease (GvHD). The presence of GvHD not only reduces animal welfare, but it can also inhibit reproducibility in research.
The limitations of standard mouse models can be overcome with the use of humanized immune system (HIS) mouse models. HIS mice are engineered to reconstitute all human immune targets, enabling a greater understanding of the human immune response, and subsequently aiding the development of more promising drug candidates.
The HIS mouse model: More relevant results
As well as providing deeper insight into the behavior of pathologies, HIS mouse models offer additional advantages over traditional mouse models. Vitally, HIS mice have stable humanization for their lifetime, while the absence of GvHD reactions leads to greater animal welfare.
The advantages that HIS mouse models offer mean that they are already driving the development of next-generation immunotherapies, including chimeric antigen receptor (CAR) T-cell therapies. Here, T cells are modified with CARs that recognize surface antigens on malignant cells. Humanized mouse models have been instrumental in the development of therapies for in vivo CAR T cell generation,2 detecting previously undiscovered roadblocks and enabling researchers to refine therapies with innovations such as the incorporation of phagocytosis-shielded lentiviral vectors (LVs).3
However, opting to implement a HIS mouse model into your study is just the beginning. The quality of the HIS mouse model you choose can drastically impact the value of your results, impacting your drug development timeline and expenditure. The method of generation — whether by irradiation or chemoablation — is perhaps the most significant. Irradiation can induce anemia in the mouse, reducing their welfare and lifespan, leading to early termination of a study. But chemoablation (where mice are transplanted with CD34+ hematopoietic stem cells) does not induce anemia, leading to improved animal welfare and more relevant results that can be studied over the entire animal’s lifespan.
Beyond the generation method, the cell source can also affect the HIS mouse model. Cells from cord blood have much higher engraftment properties than those from peripheral blood or bone marrow cells, thereby increasing the quality of the mouse. Finally, cell purity is important, as any T-cell contamination can lead to GvHD and interfere with the data generated.
Drive efficient drug development with the right model
The preclinical model is critical to successful drug development. A relevant model provides more representative data and greater insight into the interactions between the TME and the immune system, leading to the progression of the most promising treatments. Among all preclinical models, the HIS mouse model is the most advanced and detailed, recapitulating the entire human immune system in one animal.
However, different factors such as the method of generation, cell source and cell purity can affect the quality of the HIS mouse model. Selecting the highest quality HIS mouse model increases the chances of treatment success in the clinic, accelerating the development of successful oncology treatments with much shorter timelines.
About the author
Professor Patrick Nef, PhD, president and chief executive officer of TransCure bioServices SAS, has over 30 years’ experience in R&D and early drug development spanning academia, the biotechnology industry, large pharmaceutical companies, and not-for-profit public-private partnerships. In 2012, Patrick co-founded TransCure bioServices SAS in France, developing novel human immune system (HIS) and human liver mouse disease models and CRO services for immuno-oncology, infectious, inflammation and liver diseases.
1. Van Norman GA. Limitations of animal studies for predicting toxicity in clinical trials. JACC: Basic Transl Sci. 2019;4(7):845-854. doi: 10.1016/j.jacbts.2019.10.008.
2. a) Pfeiffer A, Thalheimer FB, Hartmann S, et al. In vivo generation of human CD19-CAR T cells results in B-cell depletion and signs of cytokine release syndrome. EMBO Mol Med. 2018;10(11). doi: 10.15252/emmm.201809158 b) Klichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol. 2020;38(8):947-953. doi: 10.1038/s41587-020-0462-y.
3. Ho N, Agarwal S, Milani M, Cantore A, Buchholz CJ, Thalheimer FB. In vivo generation of CAR T cells in the presence of human myeloid cells. Mol Ther - Methods Clin Dev. 2022;26:144-156. doi: 10.1016/j.omtm.2022.06.004.