Spatio-temporal biodistribution of 89 Zr-oxine labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a preclinical tumor model

Quantitative in vivo monitoring of cell biodistribution offers assessment of treatment efficacy in real-time and can provide guidance for further optimization of chimeric antigen receptor (CAR) modified cell therapy. We evaluated the utility of a non-invasive, serial Zr-oxine PET imaging to assess o...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2021-07, Vol.11 (1), p.15077
Main Authors: Sta Maria, Naomi S, Khawli, Leslie A, Pachipulusu, Vyshnavi, Lin, Sharon W, Zheng, Long, Cohrs, Daniel, Liu, Xiaodan, Hu, Peisheng, Epstein, Alan L, Jacobs, Russell E
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Male
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasms - diagnostic imaging
Neoplasms - metabolism
Oxyquinoline - metabolism
Positron-Emission Tomography - methods
Radioisotopes - metabolism
Receptors, Antigen, T-Cell - metabolism
Receptors, Chimeric Antigen - metabolism
T-Lymphocytes - metabolism
Tissue Distribution - physiology
Zirconium - metabolism
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Quantitative in vivo monitoring of cell biodistribution offers assessment of treatment efficacy in real-time and can provide guidance for further optimization of chimeric antigen receptor (CAR) modified cell therapy. We evaluated the utility of a non-invasive, serial Zr-oxine PET imaging to assess optimal dosing for huLym-1-A-BB3z-CAR T-cell directed to Lym-1-positive Raji lymphoma xenograft in NOD Scid-IL2Rgamma (NSG) mice. In vitro experiments showed no detrimental effects in cell health and function following Zr-oxine labeling. In vivo experiments employed simultaneous PET/MRI of Raji-bearing NSG mice on day 0 (3 h), 1, 2, and 5 after intravenous administration of low (1.87 ± 0.04 × 10 cells), middle (7.14 ± 0.45 × 10 cells), or high (16.83 ± 0.41 × 10 cells) cell dose. Biodistribution (%ID/g) in regions of interests defined over T1-weighted MRI, such as blood, bone, brain, liver, lungs, spleen, and tumor, were analyzed from PET images. Escalating doses of CAR T-cells resulted in dose-dependent %ID/g biodistributions in all regions. Middle and High dose groups showed significantly higher tumor %ID/g compared to Low dose group on day 2. Tumor-to-blood ratios showed the enhanced extravascular tumor uptake by day 2 in the Low dose group, while the Middle dose showed significant tumor accumulation starting on day 1 up to day 5. From these data obtained over time, it is apparent that intravenously administered CAR T-cells become trapped in the lung for 3-5 h and then migrate to the liver and spleen for up to 2-3 days. This surprising biodistribution data may be responsible for the inactivation of these cells before targeting solid tumors. Ex vivo biodistributions confirmed in vivo PET-derived biodistributions. According to these studies, we conclude that in vivo serial PET imaging with Zr-oxine labeled CAR T-cells provides real-time monitoring of biodistributions crucial for interpreting efficacy and guiding treatment in patient care.
ISSN:2045-2322