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

• Published in: Journal for immunotherapy of cancer Vol. 10; no. 2; p. e004232
• Main Authors: Sousa, Luana Guimaraes de, Rajapakshe, Kimal, Rodriguez Canales, Jaime, Chin, Renee L, Feng, Lei, Wang, Qi, Barrese, Tomas Z, Massarelli, Erminia, William, William, Johnson, Faye M, Ferrarotto, Renata, Wistuba, Ignacio, Coarfa, Cristian, Lee, Jack, Wang, Jing, Melief, Cornelis J M, Curran, Michael A, Glisson, Bonnie S
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.02.2022; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Biopsy; Cancer; Clinical/Translational Cancer Immunotherapy; Cytotoxicity; Female; Gene expression; Head & neck cancer; head and neck neoplasms; Human papillomavirus; Human papillomavirus 16 - drug effects; Human papillomavirus 16 - immunology; Humans; Immunity - immunology; immunogenicity; Immunotherapy; Lymphocytes; Male; Medical prognosis; Monoclonal antibodies; Nivolumab - pharmacology; Nivolumab - therapeutic use; Patients; Software; Targeted cancer therapy; tumor microenvironment; Tumors; vaccine; Vaccines; Variables; head and neck neoplasms; vaccine; tumor microenvironment; immunogenicity; immunotherapy
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-004232

BackgroundThe 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.MethodsPatients with advanced HPV-16+ cancer and less than two prior regimens for recurrence were enrolled to receive ISA101 (100 µg/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.ResultsTwenty-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).ConclusionsEfficacy 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-γ 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.Trial registration numberNCT02426892.