Interleukin-12 (IL-12) is a pro-inflammatory cytokine involved in the generation of an inflammatory tumor microenvironment and is critical in eliciting a productive anti-tumor immune response. It has been investigated as an anti-cancer therapeutic using various delivery routes, but intratumoral injection of plasmid IL-12 (tavokinogene telseplasmid; TAVO) followed by electroporation is a gene therapy approach that results in more sustained production of IL-12 locally with minimal systemic immune-related toxicity. Here we show that TAVO not only provides protection in the treated triple-negative breast cancer (TNBC) lesion, but also induces a systemic, abscopal effect. Single cell RNAsequencing (scRNAseq) of infiltrating immune cells shows a significant increase in both CD4 and CD8 T cells as well as dendritic cells within the treated lesions, while simultaneously decreasing a granulocytic myeloid derived suppressor population. scRNAseq allows for a detailed look into not only the overall pathway enrichment caused by TAVO treatment, but also the specific receptor-ligand interactions occurring between cell types. A combination of these analyses revealed an enrichment in the IFN-gamma induced PDL1 pathway by TAVO, typified by an increase in the interaction between PDL1 on dendritic cells and PD1 on CD8 T cells. Further, dramatic enrichment of the CXCL9/10/11/CXCR3 axis was observed, consistent with previous studies in melanoma. Analysis of paired TCR alpha and beta chains on T cells additionally demonstrated a dramatic shift in tumor infiltrating T cell (TIL) clonality and frequency. In sum, these preclinical studies identify a signature of increased antigen presentation, T cell infiltration and expansion, and a decrease in the number of granulocytes but also a particular enhancement of the PDL1 immunosuppressive pathway following TAVO treatment. Using this signature, we focus on an in-depth analysis of 2 patients from a single arm, prospective clinical trial of TAVO monotherapy (OMS-I140) in pre-treated advanced TNBC that went on to receive anti-PD-1 as their immediate next therapy with clinical anti-tumor response. Together these data support the combination of TAVO with PD1/PDL1 inhibitors while also identifying other key pathways that may enhance responsiveness in TNBC patients for whom treatment options remain limited.
Citation Format: Erika J Crosby, Hiroshi Nagata, Melinda L Telli, Chaitanya R Acharya, Irene Wapnir, Kaitlin Zablotsky, Erica Browning, Reneta Hermiz, Lauren Svenson, Donna Bannavong, Kellie Malloy, David A Canton, Chris G Twitty, Takuya Osada, Herbert Kim Lyerly. Intratumoral delivery of tavokinogene telseplasmid (plasmid IL-12) and electroporation induces an immune signature that predicts successful combination in patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-22.