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The transition from preclinical development to clinical trials is a critical, yet high-risk stage in drug development, with approximately 89% of drugs failing to progress through all phases of clinical trials. Notably, nearly half of these failures stem from unexpected and unmanageable human toxicity, with cytokine release syndrome (CRS) being a primary challenge in the development of chimeric antigen receptor (CAR) T cell therapeutics. CRS is characterized by the rapid production of inflammatory cytokines following the delivery of therapy, with symptoms ranging from mild fever to life-threatening pathology and multi-organ failure.
A significant concern with CRS in drug development is its unpredictability, both in terms of when and how severely it will manifest in humans. Traditional preclinical models, such as non-human primates, non-humanized mouse models, and in vitro systems, often fail to accurately predict CRS risks. Several therapeutic candidates that were considered safe during preclinical testing have triggered severe CRS when administered to humans in Phase I clinical trials. This highlights a critical need for preclinical models that can more accurately predict CRS and other immune-related toxicities.
The Jackson Laboratory’s CRS Evaluation Platform: Bridging the gap in safety evaluation
To bridge this translational gap in safety evaluation, The Jackson Laboratory (JAX) has developed a cutting-edge CRS Evaluation Platform to more accurately predict human immune responses to cell-based drug candidates. The platform uses mice engrafted with mature human peripheral blood mononuclear immune cells (PBMC), creating a holistic, biologically relevant model to recapitulate human-specific immune reactions. In comparison to traditional in vitro assays, JAX’s in vivo CRS Evaluation Platform delivers more reproducible and potentially translationally relevant results, providing drug developers with a more reliable preclinical safety assessment of their cellular therapies.1
JAX’s in vivo CRS Evaluation Platform delivers comprehensive preclinical CRS risk assessments through body weight and temperature monitoring, quantification of human cytokines, flow cytometry, and other assays. Researchers can also obtain tissue samples at the end of the experiment to analyze organ infiltration, liver toxicity, cardiotoxicity, neurotoxicity, and other downstream effects. The platform additionally supports concurrent efficacy testing through human tumor co-engraftment and dose ranging studies, helping define the therapeutic window and optimize clinical trial design.
By utilizing multiple PBMC donors, researchers can generate diverse datasets to mimic clinical variability, providing a more accurate and comprehensive prediction of clinical outcomes. This also provides a platform to test allogeneic CAR T cells across different patient populations, providing a comprehensive understanding of how various groups may respond to treatment. Moreover, this platform can be used to inform the design of allogeneic CAR T cells to minimize reactivity across a broad range of human immune systems.
Expanding the potential of JAX’s CRS Evaluation Platform
While testing immunomodulatory therapies is the most obvious initial use for in vivo CRS
assays, this humanized mouse platform has other far-reaching potential applications. For example, it could offer insight into underlying biological differences that predispose some individuals to develop CRS after exposure to certain infectious diseases or more broadly understand how different patient factors like age, sex, genetics, and immune history may influence CRS response.
Streamlining CAR T drug development safety
JAX’s in vivo CRS Evaluation Platform not only helps mitigate the risk of moving unsafe compounds into the clinic but also accelerates the development process by enabling more efficient and comprehensive safety evaluations. By improving preclinical CRS risk predictions, JAX’s platform helps drug developers identify and optimize promising lead candidates, and accelerate the development, testing, and refinement of new modified CAR structures.
Reference
- Ye, C., Yang, H., Cheng, M., Shultz, L. D., Greiner, D. L., Brehm, M. A., & Keck, J. G. (2020, August 9). A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic-related cytokine release syndrome. The FASEB Journal, 34(9), 12963–12975.
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