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Chimeric antigen receptor (CAR) T-cell therapy has inspired newfound hope for patients with unresponsive cancer and created widespread scientific enthusiasm spanning oncology to autoimmune disease. At the time of this writing, there are only six FDA-approved CAR T-cell therapies, primarily for oncology indications. Even though the FDA granted orphan drug designation for a CAR T-cell therapeutic for use in lupus earlier this year, there is still much work to be done to bring more drugs to market. The path to furthering these treatments requires mouse models, which can be used for proof-of-concept studies, understanding mechanisms of action, optimizing protein designs, predicting clinical outcomes, and even investigating toxicity and side effects.
Focus on potential
Like most new oncology therapies, CAR T-cell therapy still requires additional scientific investigation and refinement in the preclinical stages. Allogeneic CAR T-cell therapies—using human donor cells—could accelerate timelines and broaden distribution, but they face unique challenges, including graft-versus-host disease and cytokine release syndrome. Modeling these responses and treating any negative side effects in murine models will aid in developing more translatable treatments.
The most translatable platform: mice
Before using CAR T-cell therapies in patients, it’s essential to determine efficacy in animal models that capture disease complexities. Cell-based ex vivo assays alone are unable to recapitulate the intricacies of animal immune systems. FDA guidance issued in January 2024 emphasized the use of animal models in CAR T-cell therapy, noting, “Animal models can be useful in demonstrating proof-of-concept data for CAR T-cell functionality.” The guidance also noted, “If a relevant surrogate product is available, syngeneic tumor animal models can provide information regarding the interaction of the surrogate CAR T-cells with an intact host immune system and potential on-target/off-tumor toxicities.” As the immuno-oncology industry evolves, so must the preclinical animal models that fuel these early stages of drug development. Taconic Biosciences recognizes the importance of breaking down licensing barriers and making available the most translationally relevant preclinical models for CAR T-cell therapy development. The IL-2 NOG mouse, a super-immunodeficient mouse that expresses the human IL-2 cytokine, is one example of a complex animal model that has been successfully employed to model CAR T-cell immunotherapy in HER2+ breast cancer and is available off the shelf.1 In one recent study using hIL-2 NOG mice, researchers were able to demonstrate significant CAR T-mediated antitumor efficacy in mice transplanted with PDX melanoma cell lines. Additionally, Taconic’s immunodeficient NOG-EXL mice, which express human GM-CSF and IL-3 cytokines, were used to assess CAR T-cell therapy in non-small cell lung cancer.2 In addition to the hIL-2 NOG and NOG-EXL models, which are maintained in live colonies for easy access, Taconic has the most experienced model generation team in the industry that partners with researchers to create custom models tailored to their specific CAR T-cell therapy investigations.
Creating advanced CAR T-cell therapies requires extensive preclinical studies. However, by using animal models that approximate human disease, scientists are able to reduce the number of animals needed to elucidate how therapeutic candidates act upon disease in preclinical stages. Taconic’s commitment to the 3R’s principle—Replace, Reduce, and Refine—promotes the ethical use of animals in scientific research and exceeds U.S. FDA and international animal use guidelines. Streamlining the preclinical-to-clinical oncology pipeline necessitates effective tools capable of capturing the intricacies of disease response to treatment in humans. Super immunodeficient and genetically engineered models are uniquely valuable tools for oncology and autoimmune researchers seeking to develop novel therapeutics.
References
- Cao B, Liu M, Wang L, et al. Remodelling of tumour microenvironment by microwave ablation potentiates immunotherapy of AXL-specific CAR T-cells against non-small cell lung cancer. Nat Commun. 2022;13(1):6203. Published 2022 Oct 19. doi:10.1038/s41467-022-33968-5
- Forsberg EM, Lindberg MF, Jespersen H, Alsén S, Olofsson Bagge R, Donia M, Svane IM, Nilsson O, Ny L, Nilsson LM, Nilsson JA. HER2 CAR-T cells eradicate uveal melanoma and T cell therapy-resistant human melanoma in interleukin-2 (IL-2) transgenic NOD/SCID IL-2 receptor knockout mice. Cancer Res. 2019 Jan 8. pii: canres.3158.2018
Explore the hIL-2 NOG, NOG-EXL, and other super immunodeficient models for CAR T-cell therapy work, visit: taconic.com/gen.
