Local Radiation Enhances Systemic CAR T Cell Efficacy by Augmenting Antigen Cross-Presentation and T-cell Infiltration.

Autor:	Kostopoulos N; University of Pennsylvania, Philadelphia, Pennsylvania, United States., Costabile F; University of Pennsylvania, Philadelphia, Pennsylvania, United States., Krimitza E; University of Pennsylvania, Philadelphia, Pennsylvania, United States., Beghi S; University of Pennsylvania, Philadelphia, Pennsylvania, United States., Goia D; UPMC Hilman Cancer Center, Pittsburgh, Pennsylvania, United States., Perales-Linares R; University of Pennsylvania, Philadelphia, Pennsylvania, United States., Thyfronitis G; University of Ioannina, Ioannina, Greece., LaRiviere MJ; University of Pennsylvania, Philadelphia, Pennsylvania, United States., Chong EA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States., Schuster SJ; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States., Maity A; Huntsman Cancer Institute, Salt Lake City, Utah, United States., Koumenis C; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States., Plastaras JP; University of Pennsylvania, Philadelphia, Pennsylvania, United States., Facciabene A; University of Pennsylvania, Philadelphia, Pennsylvania, United States.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Aug 30. Date of Electronic Publication: 2024 Aug 30.
DOI:	10.1182/bloodadvances.2024012599
Abstrakt:	Chimeric antigen receptor (CAR) T cell therapy targeting CD19 (CART-19) represents a significant advance in the treatment of patients with relapsed or refractory CD19-positive B-cell lymphomas. However, a significant portion of patients either relapse or fail to respond. Moreover, many patients have symptomatic disease, requiring bridging radiation therapy (RT) during the period of CAR-T cells manufacturing. To investigate the impact of 1-2 fractions of low-dose RT on CART-19 treatment response, we developed a mouse model using A20 lymphoma cells for CART-19 therapy. We found that low dose fractionated RT had a positive effect on generating abscopal systemic antitumor responses beyond the irradiated site. The combination of RT with CART-19 therapy resulted in additive effects on tumor growth in irradiated masses. Notably, a significant additional increase in antitumor effect was observed in non-irradiated tumors. Mechanistically, our results validate activation of the cGAS/STING pathway, tumor-associated antigen (TAA) cross-priming, and elicitation of epitope spreading. Collectively, our findings suggest that RT may serve as an optimal priming and bridging modality for CAR-T cell therapy overcoming treatment resistance and improving clinical outcomes in patients with CD19-positive hematologic malignancies. (Copyright © 2024 American Society of Hematology.)
Databáze:	MEDLINE
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