Novel Transcriptional Signatures Associated with Response to Vidutolimod in Patients with Anti–PD-1-Refractory Melanoma and NSCLC

Intratumoral injection of toll-like receptor agonists induces an interferon response signature and antitumor CD8+ T-cells, improving responses to anti–PD-1 therapy. In addition, toll-like receptor 9 (TLR9)-mediated T-cell activation can induce PD-1 expression. Thus, combining TLR9 agonists with approved PD-1 blockade therapies is a rational approach to target cancer immune evasion.1

Vidutolimod is a cytidine phosphate guanosine (CpG-A) oligodeoxynucleotide packaged in a virus-like particle. It acts as a TLR9 agonist leading to the activation of plasmacytoid dendritic cells (pDC). Studies have shown that intratumoral vidutolimod alone or in combination with intravenous anti–PD-L1 has promising anticancer activity in patients with anti–PD-L1-refractory melanoma or non–small-cell lung cancer (NSCLC). The response, however, was not correlated with anti–PD-L1-related biomarkers. The aim of this study was to identify novel transcriptional signatures as potential response biomarkers to vidutolimod-based therapy.2

In this study, RNA sequencing was performed on baseline biopsies from patients with anti–PD-L1-refractory NSCLC (n = 11) treated with vidutolimod alone or in combination with anti–PD-L1 therapy. Deconvolution of immune cells was performed using TIMER2.0. Prediction models were generated using QLattice. Signatures were characterized using both publicly available bulk and single-cell RNA-Seq data sets of pDC subsets or PD-1/CTLA-4 blockade response data sets.2

The investigators identified 2 gene signatures, COPII vesicle and Golgi targeting, that were strongly correlated with response to vidutolimod.2 Leading-edge analysis of these signatures identified 35 common core genes that strongly differentiated RECIST version 1.1 responders compared with patients with progressive disease. Common core enrichment was also significantly associated with tumor shrinkage in patients with NSCLC (P = .027).2 Common core genes were significantly correlated with response to vidutolimod single-agent or combination treatment but not with clinical baseline prognostic factors or interferon-γ18.

A model based on common core genes and transcription factor ELF2 predicted response in melanoma (area under the curve, 0.93; 95% confidence interval, 0.82-1.00). In public data sets, common core genes were not associated with response to PD-1/CTLA-4 blockade but were highly expressed in the type I interferon-secreting subset of pDCs and some myeloid cells.

The investigators concluded that COPII vesicle and Golgi targeting transcriptional signatures were associated with antitumor activity of intratumoral vidutolimod in combination with anti–PD-L1 in patients with anti–PD-1-refractory melanoma or NSCLC.

References

  1. Ribas A, Medina T, Kirkwood JM, et al. Overcoming PD-1 blockade resistance with CpG-A toll-like receptor 9 agonist vidutolimod in patients with metastatic melanoma. Cancer Discov. 2021;11:2998-3007.
  2. Liu H, Zhao L, Zheng P, et al. Novel transcriptional signatures associated with antitumor activity in vidutolimod (vidu)-treated patients (pts) with anti-PD-1-refractory melanoma and non-small cell lung cancer (NSCLC). Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract LB107.

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