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Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of plasmid CXCL9 synergizes with plasmid IL-12 therapy to elicit robust anti-tumor immunity.

Publication ,  Journal Article
Lee, JY; Nguyen, B; Mukhopadhyay, A; Han, M; Zhang, J; Gujar, R; Salazar, J; Hermiz, R; Svenson, L; Browning, E; Lyerly, HK; Canton, DA ...
Published in: Mol Ther Oncolytics
June 16, 2022

Clinical studies have demonstrated that local expression of the cytokine IL-12 drives interferon-gamma expression and recruits T cells to the tumor microenvironment, ultimately yielding durable systemic T cell responses. Interrogation of longitudinal biomarker data from our late-stage melanoma trials identified a significant on-treatment increase of intratumoral CXCR3 transcripts that was restricted to responding patients, underscoring the clinical relevance of tumor-infiltrating CXCR3+ immune cells. In this study, we sought to understand if the addition of DNA-encodable CXCL9 could augment the anti-tumor immune responses driven by intratumoral IL-12. We show that localized IL-12 and CXCL9 treatment reshapes the tumor microenvironment to promote dendritic cell licensing and CD8+ T cell activation. Additionally, this combination treatment results in a significant abscopal anti-tumor response and provides a concomitant benefit to anti-PD-1 therapies. Collectively, these data demonstrate that a functional tumoral CXCR3/CXCL9 axis is critical for IL-12 anti-tumor efficacy. Furthermore, restoring or amplifying the CXCL9 gradient in the tumors via intratumoral electroporation of plasmid CXCL9 can not only result in efficient trafficking of cytotoxic CD8+ T cells into the tumor but can also reshape the microenvironment to promote systemic immune response.

Duke Scholars

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Published In

Mol Ther Oncolytics

DOI

ISSN

2372-7705

Publication Date

June 16, 2022

Volume

25

Start / End Page

174 / 188

Location

United States
 

Citation

APA
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Lee, J. Y., Nguyen, B., Mukhopadhyay, A., Han, M., Zhang, J., Gujar, R., … Twitty, C. G. (2022). Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of plasmid CXCL9 synergizes with plasmid IL-12 therapy to elicit robust anti-tumor immunity. Mol Ther Oncolytics, 25, 174–188. https://doi.org/10.1016/j.omto.2022.04.005
Lee, Jack Y., Bianca Nguyen, Anandaroop Mukhopadhyay, Mia Han, Jun Zhang, Ravindra Gujar, Jon Salazar, et al. “Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of plasmid CXCL9 synergizes with plasmid IL-12 therapy to elicit robust anti-tumor immunity.Mol Ther Oncolytics 25 (June 16, 2022): 174–88. https://doi.org/10.1016/j.omto.2022.04.005.
Lee JY, Nguyen B, Mukhopadhyay A, Han M, Zhang J, Gujar R, et al. Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of plasmid CXCL9 synergizes with plasmid IL-12 therapy to elicit robust anti-tumor immunity. Mol Ther Oncolytics. 2022 Jun 16;25:174–88.
Lee, Jack Y., et al. “Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of plasmid CXCL9 synergizes with plasmid IL-12 therapy to elicit robust anti-tumor immunity.Mol Ther Oncolytics, vol. 25, June 2022, pp. 174–88. Pubmed, doi:10.1016/j.omto.2022.04.005.
Lee JY, Nguyen B, Mukhopadhyay A, Han M, Zhang J, Gujar R, Salazar J, Hermiz R, Svenson L, Browning E, Lyerly HK, Canton DA, Fisher D, Daud A, Algazi A, Skitzki J, Twitty CG. Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of plasmid CXCL9 synergizes with plasmid IL-12 therapy to elicit robust anti-tumor immunity. Mol Ther Oncolytics. 2022 Jun 16;25:174–188.
Journal cover image

Published In

Mol Ther Oncolytics

DOI

ISSN

2372-7705

Publication Date

June 16, 2022

Volume

25

Start / End Page

174 / 188

Location

United States