Following up biomarker data from patients with late-stage melanoma treated with intratumoral (i.t.) IL-12 DNA, which showed that increases in i.t. CXCR3 transcripts correlated with treatment responses, Lee et al. investigated whether electroporating a CXCL9 DNA plasmid could boost the efficacy of i.t. IL-12. In murine tumor models, localized IL-12 and CXCL9 treatment promoted dendritic cell antigen presentation and CD8+ T cell activation, resulting in a significant abscopal tumor response and improved anti-PD-1 responses. A functional CXCR3/CXCL9 axis was required for IL-12 efficacy, which increased and stimulated efficient trafficking of CD8+ cells into the TME.
Contributed by Katherine Turner
ABSTRACT: 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.
Author Info: (1) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (2) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (3)
Author Info: (1) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (2) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (3) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (4) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (5) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (6) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (7) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (8) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (9) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (10) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (11) Department of Immunology, Duke University, Durham, NC 27710, USA. (12) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA. (13) Department of Immunology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA. (14) Department of Medicine, University of California, San Francisco, 550 16 Street, San Francisco, CA 94158, USA. (15) Department of Medicine, University of California, San Francisco, 550 16 Street, San Francisco, CA 94158, USA. (16) Department of Immunology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA. (17) Oncosec Medical Incorporated, 3565 General Atomics Court, San Diego, CA 92121, USA.
