ISA101 and nivolumab for HPV-16+ cancer: updated clinical efficacy and immune correlates of response

Background The combination of ISA101, a human papilloma virus (HPV) 16 peptide vaccine, and nivolumab showed a promising response rate of 33% in patients with incurable HPV-16(+) cancer. Here we report long-term clinical outcomes and immune correlates of response. Methods Patients with advanced HPV-16(+) cancer and less than two prior regimens for recurrence were enrolled to receive ISA101 (100 mu g/peptide) on days 1, 22, and 50 and nivolumab 3 mg/kg every 2 weeks beginning day 8 for up to 1 year. Baseline tumor samples were stained with multiplex immunofluorescence for programmed death-ligand 1 (PD-L1), programmed cell death protein-1 (PD-1), CD3, CD8, CD68, and pan-cytokeratin in a single panel and scanned with the Vectra 3.0 multispectral microscope. Whole transcriptome analysis of baseline tumors was performed with Affymetrix Clariom D arrays. Differential gene expression analysis was performed on responders versus non-responders. Results Twenty-four patients were followed for a median of 46.5 months (95% CI, 46.0 months to not reached (NR)). The median duration of response was 11.2 months (95% CI, 8.51 months to NR); three out of eight (38%) patients with objective response were without progression at 3 years. The median and 3-year overall survival were 15.3 months (95% CI, 10.6 months to 27.2 months) and 12.5% (95% CI, 4.3% to 36%), respectively. The scores for activated T cells ((CD3(+)PD-1(+))+(CD3(+)CD8(+)PD-1(+))), activated cytotoxic T cells (CD3(+)CD8(+)PD-1(+)), and total macrophage ((CD68(+)PD-L1(-))+(CD68(+)PD-L1(+))) in tumor were directly correlated with clinical response (p<0.05) and depth of response with the two complete response patients having the highest degree of CD8(+) T cells. Gene expression analysis revealed differential regulation of 357 genes (>= 1.25 fold) in non-responders versus responders (p<0.05). Higher expression of immune response, inflammatory response and interferon-signaling pathway genes were correlated with clinical response (p<0.05). Conclusions Efficacy of ISA101 and nivolumab remains promising in long-term follow-up. Increased infiltration by PD-1(+) T cells and macrophages was predictive of response. Enrichment in gene sets associated with interferon-gamma response and immune infiltration strongly predicted response to therapy. A randomized trial is ongoing to test this strategy and to further explore correlates of immune response with combined nivolumab and ISA101, versus nivolumab alone.

Automated summary

The combination of ISA101 and nivolumab shows promising long-term clinical outcomes in patients with incurable HPV-16(+) cancer. Increased infiltration of CD8(+) T cells and macrophages is predictive of treatment response.