| Autor: |
Vipul Bansal, Phillip K. Darcy, James C. Korte, Jeanne Butler, Lucy Kravets, Samuel R. Anderson, Ritu Singla, Ben Solomon, Simon J. Harrison, Timothy M. Cain, Gerard McKiernan, Ravi Shukla, Dominic Wall, Jyoti Arora, M. Wright, Nicholas Zia, Paul J Neeson, Rodney J. Hicks, Rajesh Ramanathan, Amanda Gammilonghi, Carleen Cullinane |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Cytotherapy. 22:S201 |
| ISSN: |
1465-3249 |
| DOI: |
10.1016/j.jcyt.2020.04.074 |
| Popis: |
Background & Aim This is a first in human in-vivo biodistribution of ex-vivo labelled CAR T cells assessed in a cohort of patients. Cells were labelled with novel Cu-64 labelled superparamagnetic iron oxide nanoparticles (SPION) and infused IV into patients with solid tumors & tracked using clinical dual PET-MR. The study validates the clinical translation of CAR T cell in-vivo tracking in real time. Methods, Results & Conclusion Methods Cu-64 radioisotope was bound to silica coated SPION using electrolysis plating with tin & palladium seeding. Cellular uptake of Cu-64 SPION was facilitated with a transfecting agent. Functional assays including 51Chromium release, cytometric bead array demonstrated that labelling process did not affect cytotoxicity & cytokine secretion (TNFα & IFN-g). T cells were transduced with retroviral vector constructs encoding for second-generation chimeric T-cell receptor specific for carbohydrate Lewis Y antigen. Modified T-cells were expanded ex-vivo & were labelled with Cu-64 (∼300 MBq) prior to re-infusion (3 × 108 labelled cells). Scanning is performed with Siemens 3T dual PET-MR scanner. Results In this first in human in-vivo study (HREC/16/PMCC/30) a cohort of patients received ex-vivo labelled CAR T cells to determine how many labelled cells distribute to various body organs and lesions within first 3-5 days. Our results demonstrate that both fresh (N =3) and thawed cells (N =3) can be efficiently labelled in the range of 40% - 80% with high cell viability (≥90%). An observed trend in SUVmean provided insight into efficacy & individual response to therapy. Early time points showed moderate uptake of labelled cells in lungs posterior basal segments without increased activity over next few days, suggesting a transient process. Mild, diffuse bone marrow & relatively intense uptake of labelled cells in liver & spleen suggests margination of cells to reticulo-endothelial system. Excretion via hepatobiliary indicated reabsorption from GI tract & re-circulation of labelled cells. The initial data shows that labelled cell may remain with in the system for upto 10-15 days. Minimal uptake in brain & heart supported safety profile of labeling agent. Conclusions This is first in human in-vivo study to provide highly valuable visual and dynamic data in real time and provides insight into individual responses to therapy. CAR T cell functionality largely remain unchanged due to labeling process. The findings indicate that labelled cells remain persistent for extended period of time. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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