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Published on: December 12, 2018
Hypoxic 3D Tumor Model for Evaluating of CAR-T Cell Therapy In Vitro
Jeong Min Oh1, Keyue Shen2,3
1Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA.
Abstract:
Solid tumors contain abnormal physical and biochemical barriers that hinder chimeric antigen receptor (CAR) T cell therapies. However, there is a lack of understanding on how the solid tumor microenvironment (e.g. hypoxia) modulates CAR-T cell function. Hypoxia is a common feature of many advanced solid tumors that contributes to reprogramming of cancer and T cell metabolism as well as their phenotypes and interactions. To gain insights into the activities of CAR-T cells in solid tumors and to assess the effectiveness of new combination treatments involving CAR-T cells, in vitro models that faithfully reflect CAR-T cell-solid tumor interactions under physiologically relevant tumor microenvironment is needed. Here we demonstrate how to establish a hypoxic 3-dimensional (3-D) tumor model using a cleanroom-free, micromilling-based microdevice and assess the efficacy of the combination treatment with CAR-T cells and PD-1/PD-L1 inhibition.
Insights
This study introduces a novel 3D tumor model to investigate how hypoxia affects chimeric antigen receptor (CAR) T cell therapy in solid tumors. It assesses combination treatments involving CAR T-cells and PD-1/PD-L1 inhibition.
Area of Science:
- Oncology
- Immunology
- Biomedical Engineering
Background:
- Solid tumors present physical and biochemical barriers impeding chimeric antigen receptor (CAR) T cell therapies.
- The solid tumor microenvironment, particularly hypoxia, significantly alters cancer and T cell metabolism, phenotypes, and interactions, yet its precise impact on CAR T cell function remains poorly understood.
Purpose of the Study:
- To develop and validate an in vitro 3D tumor model that accurately simulates the hypoxic conditions found in solid tumors.
- To investigate the functional modulation of CAR T cells within this physiologically relevant microenvironment.
- To evaluate the efficacy of combination therapies involving CAR T cells and PD-1/PD-L1 inhibition in this model.
Main Methods:
- Establishment of a hypoxic 3-dimensional (3-D) tumor model utilizing a cleanroom-free, micromilling-based microdevice.
- Assessment of CAR T cell interactions and function within the developed 3-D hypoxic tumor model.
- Evaluation of the therapeutic efficacy of combining CAR T cells with PD-1/PD-L1 inhibition.
Main Results:
- Successfully established a functional hypoxic 3-D tumor model suitable for studying CAR T cell therapy.
- Demonstrated the model's utility in assessing CAR T cell behavior under simulated solid tumor conditions.
- Provided preliminary data on the efficacy of combined CAR T cell and PD-1/PD-L1 inhibition strategies.
Conclusions:
- The developed hypoxic 3-D tumor model serves as a valuable tool for understanding CAR T cell therapy in solid tumors.
- This model facilitates the assessment of novel combination treatments, such as CAR T cells with PD-1/PD-L1 inhibition, in a physiologically relevant context.
