Humanized Mouse Models for Immune Cell Therapy Safety
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Solution Overview
Problem
Current adoptive cell therapies, such as CAR T cell therapy, often result in cytokine release syndrome (CRS) and neurotoxicity, which can lead to significant morbidity and mortality, and there is a lack of preclinical models to effectively screen for safety and efficacy of universal allogeneic engineered immune cell therapies.
Innovation Solution
A method involving the administration of human immune cells and peripheral blood mononuclear cells (PBMCs) to immunodeficient mice engrafted with diseased human cells, to assay for symptoms of CRS and efficacy of the human immune cells, allowing for the identification of agents effective for CRS treatment and the evaluation of engineered immune cells for therapeutic effectiveness without inducing CRS.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If engineered immune cells (CAR T cells, CAR NK cells) are administered to treat cancer, then anti-tumor efficacy is improved, but cytokine release syndrome (CRS) and neurotoxicity occur leading to morbidity and mortality
Solution Approach 1:
Humanized mouse models serve as an intermediary system between in vitro experiments and human clinical trials. These models contain human immune cells, human tumor cells, and human cytokine receptors, allowing the study of CRS pathogenesis and testing of anti-cytokine therapies in a physiologically relevant system before human application
Solution Approach 2:
The patent creates a copied human physiological system in mice by engrafting human immune cells, human tumor cells, and human cytokine receptors into immunodeficient mice. This humanized model copies the essential components of the human immune system and tumor microenvironment, enabling preclinical assessment of both anti-tumor efficacy and CRS toxicity
2Reliability
If preclinical models are developed to screen for CRS treatment, then safety assessment is improved, but model development complexity and time requirements increase
Solution Approach 1:
Humanized mouse models are prepared in advance with engrafted human immune cells and human tumor cells before conducting therapy assessments. This preliminary establishment of the humanized system allows subsequent rapid testing of multiple engineered immune cell products and anti-cytokine therapies without repeated model development
Solution Approach 2:
The humanized mouse model serves multiple functions simultaneously: it assesses anti-tumor efficacy, evaluates CRS toxicity, and screens anti-cytokine therapies. This multi-functional platform reduces the need for separate models for each assessment type, thereby reducing overall complexity and time requirements
Data Source
AI summary
Provided herein are humanized mouse models and methods for determining whether administration of engineered immune cell therapies likely elicit cytokine release syndrome and/or determining the efficacy of an anti-disease therapy. Further, the models provided herein may be used to test the efficacy of different anti-CRS therapies.