Journal
MOLECULAR THERAPY-ONCOLYTICS
Volume 25, Issue -, Pages 174-188Publisher
CELL PRESS
DOI: 10.1016/j.omto.2022.04.005
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Funding
- OncoSec Medical Incorporated
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This study demonstrates that localized IL-12 and CXCL9 treatment can reshape the tumor microenvironment, promote immune cell activation, and induce anti-tumor responses. Additionally, this combination treatment shows synergy with anti-PD-1 therapies.
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.
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