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Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer
Published on: October 4, 2022
Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of
Brendan Hagerty1,2, T Norene O'Sullivan3, Xianyu Zhang1
1Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
Abstract:
Antibody-based therapies designed for human use frequently fail to cross-react with the murine isoform of their target. Because of this problem, preclinical studies of antibody-based mesothelin (Msl)-targeted therapeutics in immunocompetent systems have been limited by the lack of suitable mouse models. Here, we describe two immunocompetent humanized mesothelin transgenic mouse lines that can act as tolerant hosts for C57Bl/6-syngeneic cell lines expressing the human isoform of mesothelin. Thyroid peroxidase (TPO) mice have thyroid-restricted human mesothelin expression. Mesothelin (Msl) mice express human mesothelin in the typical serosal membrane distribution and can additionally be utilized to assess on-target, off-tumor toxicity of human mesothelin-targeted therapeutics. Both transgenic strains shed human mesothelin into the serum like human mesothelioma and patients with ovarian cancer, and serum human mesothelin can be used as a blood-based surrogate of tumor burden. Using these models, we examined the on-target toxicity and antitumor activity of human mesothelin-targeted recombinant immunotoxins. We found that immunotoxin treatment causes acute and chronic histologic changes to serosal membranes in Msl mice, while human mesothelin-expressing thyroid follicular cells in TPO mice are resistant to immunotoxin despite excellent drug delivery. Furthermore, poor delivery of immunotoxin to syngeneic orthotopic human mesothelin-expressing pancreatic adenocarcinoma limits antitumor activity both alone and in combination with immune checkpoint inhibition. In summary, we have developed two high-fidelity, immunocompetent murine models for human cancer that allow for rigorous preclinical evaluation of human mesothelin-targeted therapeutics.
Insights
New mouse models enable testing of human mesothelin-targeted therapies. These immunocompetent models mimic human cancers, allowing researchers to evaluate antibody-based treatments and their toxicity in preclinical studies.
Area of Science:
- Oncology
- Immunology
- Translational Medicine
Background:
- Human antibody therapies often lack cross-reactivity with mouse targets, hindering preclinical research.
- Existing immunocompetent models are insufficient for evaluating mesothelin-targeted therapeutics.
Purpose of the Study:
- To develop and characterize immunocompetent humanized mesothelin transgenic mouse models.
- To assess the utility of these models for evaluating mesothelin-targeted therapeutics, including toxicity and efficacy.
Main Methods:
- Generation of two humanized mesothelin transgenic mouse lines (TPO and Msl mice).
- Utilized C57Bl/6-syngeneic cell lines expressing human mesothelin.
- Administered human mesothelin-targeted recombinant immunotoxins to assess on-target toxicity and antitumor activity.
Main Results:
- Both mouse models express human mesothelin and shed it into serum, mirroring human cancer patients.
- Immunotoxin treatment induced toxicity in Msl mice but showed resistance in TPO mice.
- Limited antitumor activity was observed in pancreatic adenocarcinoma models due to poor drug delivery.
Conclusions:
- Developed high-fidelity, immunocompetent murine models for human cancer research.
- These models facilitate rigorous preclinical evaluation of human mesothelin-targeted therapeutics.
- Model utility extends to assessing on-target, off-tumor toxicity and therapeutic efficacy.
