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Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography
Published on: February 17, 2022
Multiparameter Longitudinal Imaging of Immune Cell Activity in Chimeric Antigen Receptor T Cell and Checkpoint
Jinghang Xie1, Fadi El Rami1, Kaixiang Zhou1
1Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California 94305, United States.
Abstract:
Longitudinal multimodal imaging presents unique opportunities for noninvasive surveillance and prediction of treatment response to cancer immunotherapy. In this work we first designed a novel granzyme B activated self-assembly small molecule, G-SNAT, for the assessment of cytotoxic T lymphocyte mediated cancer cell killing. G-SNAT was found to specifically detect the activity of granzyme B within the cytotoxic granules of activated T cells and engaged cancer cells in vitro. In lymphoma tumor-bearing mice, the retention of cyanine 5 labeled G-SNAT-Cy5 correlated to CAR T cell mediated granzyme B exocytosis and tumor eradication. In colorectal tumor-bearing transgenic mice with hematopoietic cells expressing firefly luciferase, longitudinal bioluminescence and fluorescence imaging revealed that after combination treatment of anti-PD-1 and anti-CTLA-4, the dynamics of immune cell trafficking, tumor infiltration, and cytotoxic activity predicted the therapeutic outcome before tumor shrinkage was evident. These results support further development of G-SNAT for imaging early immune response to checkpoint blockade and CAR T-cell therapy in patients and highlight the utility of multimodality imaging for improved mechanistic insights into cancer immunotherapy.
Insights
A new imaging agent, G-SNAT, detects T cell activity for cancer immunotherapy. Multimodal imaging predicts treatment response before tumor shrinkage, aiding drug development.
Area of Science:
- Immunology
- Oncology
- Medical Imaging
Background:
- Cancer immunotherapy effectiveness relies on T cell activity, but early noninvasive monitoring remains challenging.
- Predicting treatment response requires understanding immune cell dynamics and cytotoxic function.
Purpose of the Study:
- To develop a novel imaging agent (G-SNAT) for assessing cytotoxic T lymphocyte (CTL) activity.
- To evaluate G-SNAT's utility in predicting immunotherapy response using longitudinal multimodal imaging.
Main Methods:
- Designed and characterized granzyme B-activated self-assembly small molecule (G-SNAT).
- Assessed G-SNAT's specificity for granzyme B in vitro.
- Utilized G-SNAT-Cy5 and bioluminescence imaging in mouse models of lymphoma and colorectal cancer treated with immunotherapy (anti-PD-1, anti-CTLA-4, CAR T cells).
Main Results:
- G-SNAT specifically detected granzyme B activity in activated T cells and engaged cancer cells.
- G-SNAT-Cy5 retention correlated with CAR T cell-mediated granzyme B release and tumor eradication in lymphoma models.
- Longitudinal imaging revealed immune cell dynamics predicted therapeutic outcomes in colorectal cancer models before tumor shrinkage.
Conclusions:
- G-SNAT is a promising tool for imaging early immune responses to cancer immunotherapies like checkpoint blockade and CAR T-cell therapy.
- Multimodal imaging provides mechanistic insights and predicts treatment response, supporting clinical translation.
