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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

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.

Online: http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-20-3944

Issue: Clin Cancer Res. 2021 May 1;27(9):2481-2493.


Purpose: 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.

Patients and Methods: 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.

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 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.

Conclusions: 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.