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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. | LitMetric

AI Article Synopsis

  • Triple-negative breast cancer (TNBC) is a tough condition to treat, with few options available, but a new therapy using an intratumoral IL12 plasmid (Tavo) shows promise in enhancing immune response.
  • * In mouse models and a clinical trial, Tavo was found to boost T-cell activity and improve treatment outcomes in patients who previously didn't respond to standard therapies like PD-1/PD-L1 blockers.
  • * The study identified a specific gene signature tied to better clinical results, suggesting Tavo could help convert nonresponsive tumors and improve responses across different cancer types.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102331PMC
http://dx.doi.org/10.1158/1078-0432.CCR-20-3944DOI Listing

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