Comparative Study of the Effect of Radiation Delivered by Lutetium-177 or Actinium-225 on Anti-GD2 Chimeric Antigen Receptor T Cell Viability and Functions.
In: Cancers, Jg. 16 (2024), Heft 1, S. 191-201
Online
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Zugriff:
Simple Summary: Low-dose radiation delivered by radionuclides stimulates an immune response against cancer. We hypothesize that this type of low-dose radiation can potentiate chimeric antigen receptor (CAR) T cell therapy against solid tumors. Before evaluating the combination of these therapies in vivo, we aim to determine the impacts of this type of low-dose radiation on CAR T cell viability and functions to guide the selection of the type of radionuclide (actinium-225 or lutetium-177), the dose of radiation (1, 2 or 6 Gy) and how to best sequence their administration. It follows that increasing the radiation dose results in lower CAR T cell viability while enhancing their killing potential to the same extent. At a similar dose, radiation delivered by actinium-225 is more toxic to CAR T cells than lutetium-177. This suggests that 1 or 2 Gy delivered by lutetium-177 may be optimal for in vivo combination studies with CAR T cells. Background and purpose. Chimeric antigen receptor (CAR) T cells have been relatively ineffective against solid tumors. Low-dose radiation which can be delivered to multiple sites of metastases by targeted radionuclide therapy (TRT) can elicit immunostimulatory effects. However, TRT has never been combined with CAR T cells against solid tumors in a clinical setting. This study investigated the effects of radiation delivered by Lutetium-177 ( 177 Lu) and Actinium-225 ( 225 Ac) on the viability and effector function of CAR T cells in vitro to evaluate the feasibility of such therapeutic combinations. After the irradiation of anti-GD2 CAR T cells with various doses of radiation delivered by 177 Lu or 225 Ac, their viability and cytotoxic activity against GD2-expressing human CHLA-20 neuroblastoma and melanoma M21 cells were determined by flow cytometry. The expression of the exhaustion marker PD-1, activation marker CD69 and the activating receptor NKG2D was measured on the irradiated anti-GD2 CAR T cells. Both 177 Lu and 225 Ac displayed a dose-dependent toxicity on anti-GD2 CAR T cells. However, radiation enhanced the cytotoxic activity of these CAR T cells against CHLA-20 and M21 irrespective of the dose tested and the type of radionuclide. No significant changes in the expression of PD-1, CD69 and NKG2D was noted on the CAR T cells following irradiation. Given a lower CAR T cell viability at equal doses and an enhancement of cytotoxic activity irrespective of the radionuclide type, 177 Lu-based TRT may be preferred over 225 Ac-based TRT when evaluating a potential synergism between these therapies in vivo against solid tumors. [ABSTRACT FROM AUTHOR]
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Titel: |
Comparative Study of the Effect of Radiation Delivered by Lutetium-177 or Actinium-225 on Anti-GD2 Chimeric Antigen Receptor T Cell Viability and Functions.
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Autor/in / Beteiligte Person: | Sodji, Quaovi H. ; Forsberg, Matthew H. ; Cappabianca, Dan ; Kerr, Caroline P. ; Sarko, Lauren ; Shea, Amanda ; Adam, David P. ; Eickhoff, Jens C. ; Ong, Irene M. ; Hernandez, Reinier ; Weichert, Jamey ; Bednarz, Bryan P. ; Saha, Krishanu ; Sondel, Paul M. ; Capitini, Christian M. ; Morris, Zachary S. |
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Zeitschrift: | Cancers, Jg. 16 (2024), Heft 1, S. 191-201 |
Veröffentlichung: | 2024 |
Medientyp: | academicJournal |
ISSN: | 2072-6694 (print) |
DOI: | 10.3390/cancers16010191 |
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