Intratumoral Plasmid IL12 Expands CD8 + T Cells and Induces a CXCR3 Gene Signature in Triple-negative Breast Tumors that Sensitizes Patients to Anti-PD-1 Therapy

• Published in: Clinical cancer research 2021-05, Vol.27 (9), p.2481-2493
• Main Authors: Telli, Melinda L, Nagata, Hiroshi, Wapnir, Irene, Acharya, Chaitanya R, Zablotsky, Kaitlin, Fox, Bernard A, Bifulco, Carlo B, Jensen, Shawn M, Ballesteros-Merino, Carmen, Le, Mai Hope, Pierce, Robert H, Browning, Erica, Hermiz, Reneta, Svenson, Lauren, Bannavong, Donna, Jaffe, Kim, Sell, Jendy, Foerter, Kellie Malloy, Canton, David A, Twitty, Christopher G, Osada, Takuya, Lyerly, H Kim, Crosby, Erika J
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Disease Management; Disease Models, Animal; Drug Resistance, Neoplasm - genetics; Electroporation; Female; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunophenotyping; Injections, Intralesional; Interleukin-12 - genetics; Iron Compounds; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Melanoma - therapy; Mice; Plasmids - administration & dosage; Plasmids - genetics; Receptors, CXCR3 - genetics; Treatment Outcome; Triple Negative Breast Neoplasms - etiology; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - therapy
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-3944

Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Antibodies targeting programmed cell death protein 1 (PD-1)/PD-1 ligand 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. Using mouse models of TNBC, we evaluate immune activation and tumor targeting of intratumoral IL12 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 datasets. 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 pretreatment and posttreatment 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. These data show a safe, effective intratumoral therapy that can enhance antigen presentation and recruit CD8 T cells, which are required for the antitumor efficacy. We identify a Tavo treatment-related gene signature associated with improved outcomes and conversion of nonresponsive tumors, potentially even beyond TNBC.