Intratumoral plasmid IL-12 expands CD8+ T cells and induces a CXCR3 gene signature in triple-negative breast tumors that sensitizes patients to anti-PD-1 therapy. Clinical cancer research : an official journal of the American Association for Cancer Research Telli, M. L., Nagata, H., Wapnir, I. L., Acharya, C., Zablotsky, K. E., Fox, B. A., Bifulco, C. B., Jensen, S. M., Ballesteros-Merino, C., Le, M. H., Pierce, R. H., Browning, E., Hermiz, R., Svenson, L., Bannavong, D., Jaffe, K., Sell, J., Malloy Foerter, K., Canton, D. A., Twitty, C. G., Osada, T., Lyerly, H. K., Crosby, E. J. 2021


PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Antibodies targeting PD-1/PD-L1 have entered the therapeutic landscape in TNBC, but only a minority of patients benefit. A way to reliably enhance immunogenicity, T cell infiltration, and predict responsiveness is critically needed.EXPERIMENTAL DESIGN: Utilizing mouse models of TNBC, we evaluate immune activation and tumor targeting of intratumoral IL-12 plasmid followed by electroporation (tavokinogene telseplasmid; Tavo). We further present a single arm, prospective clinical trial of Tavo monotherapy in patients with treatment refractory, advanced TNBC (OMS-I140). Finally, we expand these findings using publicly available breast cancer and melanoma data sets.RESULTS: Single cell RNA sequencing of murine tumors identified a CXCR3 gene signature (CXCR3-GS) following Tavo treatment associated with enhanced antigen presentation, T cell infiltration and expansion, and PD-1/PD-L1 expression. Assessment of pre- and post-treatment tissue from patients confirms enrichment of this CXCR3-GS in tumors from patients that exhibited an enhancement of CD8+ T cell infiltration following treatment. One patient, previously unresponsive to anti-PD-L1 therapy, but who exhibited an increased CXCR3-GS after Tavo treatment, went on to receive additional anti-PD-1 therapy as their immediate next treatment after OMS-I140, and demonstrated a significant clinical response.CONCLUSIONS: These data show a safe, effective intratumoral therapy that can enhance antigen presentation and recruit CD8 T cells, which are required for the anti-tumor efficacy. We identify a Tavo treatment-related gene signature associated with improved outcomes and conversion of non-responsive tumors, potentially even beyond TNBC.

View details for DOI 10.1158/1078-0432.CCR-20-3944

View details for PubMedID 33593880