Humanized Mouse Models Using T Cell-Negative Fractions for CRS Assessment
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Solution Overview
Problem
Current immune cell therapies, such as CAR T cell and CAR NK cell therapy, face challenges with cytokine release syndrome (CRS) and encephalopathy syndrome, which can lead to significant morbidity and mortality, and there is a lack of effective preclinical models to assess these side effects without interfering with the anti-tumor efficacy.
Innovation Solution
Utilizing T cell-negative fractions from cancer patients to humanize immunodeficient mice, allowing for the development of mouse models that accurately replicate CRS and enable assessment of therapeutic agents for efficacy and side effects, while minimizing graft-versus-host disease (GVHD) risk.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If T cell-negative fraction is used to humanize immunodeficient mice, then the risk of graft-versus-host disease (GVHD) is minimized, but the model's ability to fully replicate human immune responses is reduced
Solution Approach 1:
The invention extracts and removes T cells from the PBMC sample before humanizing the mice. By depleting T cells from the donor PBMCs, the method eliminates the harmful GVHD effect while preserving other immune cell types (B cells, monocytes, NK cells) that contribute to immune responses without causing graft-versus-host disease.
Solution Approach 2:
The patent uses an intermediary approach by introducing non-T cell immune components from human donors into immunodeficient mice. These human immune cells serve as intermediaries that can produce human cytokines and mount human-like immune responses without directly causing GVHD, enabling safer preclinical testing of CRS therapies.
2Measurement precision
If traditional preclinical models are used to assess CRS, then the models can detect cytokine release, but they interfere with anti-tumor efficacy and do not accurately predict human CRS
Solution Approach 1:
The invention creates a copied human immune system within mice by humanizing immunodeficient mice with human PBMCs (T cell-depleted). This humanized model copies human immune responses in a murine host, allowing accurate detection of human-like CRS responses to engineered immune cells without the confounding effects seen in traditional mouse models.
Solution Approach 2:
The patent changes the fundamental parameter of the model system by transitioning from traditional murine models to humanized mouse models. This parameter change enables the system to detect human-specific cytokine profiles and immune responses while maintaining the practical advantages of mouse models for preclinical testing.
3Productivity
If T cells are collected from cancer patients for therapy, then sufficient cell numbers are obtained for treatment, but the leftover fraction is discarded as waste despite containing valuable immune cells
Solution Approach 1:
The invention applies the discarding and recovering principle by taking the fraction of blood components that would normally be discarded after T cell apheresis collection and recovering valuable immune cells from it. The T cell-negative fraction, which contains B cells, monocytes, NK cells, and other immune cells, is rescued and used to humanize mice for preclinical testing, converting waste into a valuable resource.
Solution Approach 2:
The patent enables the waste fraction to serve a useful purpose by using it to create humanized mouse models that can test the very therapies being developed. The leftover immune cells from patient apheresis find new life in supporting preclinical research, allowing the system to self-validate and reduce waste simultaneously.
Data Source
AI summary
Provided herein are humanized mouse models generated using T cell-negative fractions or peripheral blood mononuclear cells obtained from T cell-negative fractions, and methods of using the mouse models to assess the efficacy and/or side effects of a therapeutic agent. Immune cell therapies require a large number of cells. Most commonly, the cells are collected using a process referred to as apheresis. Apheresis collection of the mononuclear cell (MNC) layer has been shown to be a safe and efficient method of collecting the large number of T cells.