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Tuning the Antigen Density Requirement for CAR T-cell Activity
Robbie G Majzner1,2, Skyler P Rietberg2, Elena Sotillo2
1Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
Cancer Discovery
|March 21, 2020
Summary
Chimeric antigen receptor (CAR) T-cell therapy faces challenges with low-antigen-density tumors. Optimizing CAR construct design, particularly the CD28 hinge-transmembrane region, can improve T-cell recognition and persistence against these difficult targets.
Area of Science:
- Immunology
- Cancer Biology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy shows promise but faces resistance due to insufficient reactivity against cancer cells with low antigen density.
- Understanding the factors that influence the antigen recognition threshold for CAR T-cells is crucial for improving therapeutic efficacy.
Purpose of the Study:
- To investigate how CAR construct design modulates antigen recognition thresholds.
- To compare the efficacy of different CAR constructs against tumors with varying antigen densities.
- To explore strategies for re-engineering CAR T-cells to overcome resistance in low-antigen-density tumors.
Main Methods:
- Comparative analysis of CD19 CAR constructs (axicabtagene ciloleucel vs. tisagenlecleucel) against antigen-low tumor models.
- Modulation of CAR signaling strength by altering immunoreceptor tyrosine-based activation motifs (ITAMs).
- Investigating the impact of hinge-transmembrane (H/T) regions (CD8 vs. CD28) on CAR T-cell function and immunologic synapse formation.
Main Results:
- CAR T-cell activity is significantly dependent on target antigen density.
- Axicabtagene ciloleucel (CD19-CD28ζ) demonstrated superior activity against antigen-low tumors compared to tisagenlecleucel (CD19-4-1BBζ).
- Enhancing ITAMs increased CAR T-cell recognition of low-antigen-density cells, while ITAM deletions increased the antigen threshold. Replacing the CD8 H/T region with CD28 H/T in a 4-1BBζ CAR lowered the reactivity threshold and improved synapse stability.
Conclusions:
- CAR T-cell efficacy against tumors is critically influenced by antigen density.
- CAR construct engineering, specifically the hinge-transmembrane region and ITAM content, can precisely tune antigen recognition thresholds.
- Strategies exist to enhance 4-1BBζ-based CAR T-cells for improved recognition of low-antigen-density tumors while preserving their persistence advantage.
