Clinical Trial

. 2022 Feb;10(2):e004232.

doi: 10.1136/jitc-2021-004232.

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

Luana Guimaraes de Sousa¹, Kimal Rajapakshe², Jaime Rodriguez Canales³, Renee L Chin^{4

5}, Lei Feng⁶, Qi Wang⁷, Tomas Z Barrese⁸, Erminia Massarelli⁹, William William¹⁰, Faye M Johnson¹, Renata Ferrarotto¹, Ignacio Wistuba¹¹, Cristian Coarfa¹², Jack Lee¹³, Jing Wang⁷, Cornelis J M Melief¹⁴, Michael A Curran^#^{15

5}, Bonnie S Glisson^#¹

Affiliations

¹ The University of Texas MD Anderson Cancer Center Department of Thoracic Head and Neck Medical Oncology, Houston, Texas, USA.
² Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³ Translational Medicine, AstraZeneca, Gaithersburg, Maryland, USA.
⁴ Department of Immunology and Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁵ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁶ Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁷ Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁸ Grupo Fleury, Sao Paulo, Brazil.
⁹ Medical Oncology, City of Hope National Medical Center, Duarte, California, USA.
¹⁰ Departmento de Oncologia e Hematologia, Centro Oncológico BP Beneficência Portuguesa de São Paulo, Sao Paulo, Brazil.
¹¹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹² Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
¹³ Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹⁴ ISA Pharmaceuticals, Leiden, The Netherlands.
¹⁵ Department of Immunology and Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA mcurran@mdanderson.org.

^# Contributed equally.

PMID: 35193933
PMCID: PMC9066369
DOI: 10.1136/jitc-2021-004232

Clinical Trial

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

Luana Guimaraes de Sousa et al. J Immunother Cancer. 2022 Feb.

. 2022 Feb;10(2):e004232.

doi: 10.1136/jitc-2021-004232.

Authors

Affiliations

¹ The University of Texas MD Anderson Cancer Center Department of Thoracic Head and Neck Medical Oncology, Houston, Texas, USA.
² Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³ Translational Medicine, AstraZeneca, Gaithersburg, Maryland, USA.
⁴ Department of Immunology and Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁵ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁶ Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁷ Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁸ Grupo Fleury, Sao Paulo, Brazil.
⁹ Medical Oncology, City of Hope National Medical Center, Duarte, California, USA.
¹⁰ Departmento de Oncologia e Hematologia, Centro Oncológico BP Beneficência Portuguesa de São Paulo, Sao Paulo, Brazil.
¹¹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹² Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
¹³ Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹⁴ ISA Pharmaceuticals, Leiden, The Netherlands.
¹⁵ Department of Immunology and Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA mcurran@mdanderson.org.

^# Contributed equally.

PMID: 35193933
PMCID: PMC9066369
DOI: 10.1136/jitc-2021-004232

Abstract

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 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.

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-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 number: NCT02426892.

Keywords: head and neck neoplasms; immunogenicity; immunotherapy; tumor microenvironment; vaccine.

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Conflict of interest statement

Competing interests: RF: reports personal fees from Regeneron-Sanofi, Ayala Pharmaceuticals, Klus Pharma, Bicara Therapeutics, Medscape, Carevive systems, G1 Therapeutics, Prelude Therapeutics, Merck, and Intellisphere in the past 36 months outside of the submitted work; and institutional fees from AstraZeneca, Merck, Genentech, Pfizer, Rakuten, Nanobiotix, and EMD Serono in the past 36 months. WW has received honoraria/speaker’s fees and/or participated in advisory boards from Roche/Genentech, Bristol Myers Squibb, Eli Lilly, Merck, AstraZeneca, Pfizer, Takeda, Janssen, Boehringer Ingelheim, Novartis, Sanofi Aventis. CJMM is Chief Scientific Officer of ISA Pharmaceuticals, a biotech company aiming at registration of a long peptide vaccine very similar to the one studied in this manuscript. MAC reports grants and personal fees from ImmunoGenesis, Inc. and ImmunoMet, Inc., personal fees from Alligator Bioscience, Inc., ImmunOS, Inc., Oncoresponse, Inc., Pieris, Inc., Nurix, Inc., Aptevo, Inc., Servier, Inc., Kineta, Inc., Salarius, Inc., Xencor, Inc., Agenus, Inc., Mereo, Inc., Astrazeneca, Inc., Amunix, Inc., Adagene, Inc., outside the submitted work; In addition, Dr. Curran has a patent Methods and Composition for Localized Secretion of Anti-CTLA-4 Antibodies with royalties paid by multiple licensees, a patent Dual specificity antibodies which bind both PD-L1 and PD-L2 and prevent their binding to PD-1 with royalties paid by ImmunoGenesis, Inc. IIW reports consults fees from ROCHE, Bayer, BMS, Astra Zeneca, Pfizer, HTG molecular, Merck, ClaxoSmithKline, Guardant Health, Novartis, Flame, Sanofi, Janssen, Daiichi Sankyo, Oncocyte, Amgen, MSD, Medcape; honoraria from Medscape, Roche, Pfizer, AstraZeneca, Platform Health, Merck; and Grants from Genetech, HTG Molecular, Merck, BMS, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, Akova. JJL reports he received grant from Cancer Center Support Grant (CCSG) P30 CA016672 from National Cancer Institute. BG reports consult fees from Regeneron and grants from Pfizer Inc, ISA Pharmaceuticals, and Medimmune.

Figures

**Figure 1**
Treatment response and survival. (A) Duration of response for each patient (blue bars). The asterisk indicates a patient with response ongoing who died from a non-cancer related cause (intracranial hemorrhage). (B) and (C) are Kaplan-Meier curves for progression free-survival (PFS) and overall survival (OS), respectively. CR, complete response; OPSCC, oropharyngeal squamous cell carcinoma.

**Figure 2**
Tumor immune microenvironment. (A), (B) and (C): Comparison of immune cell-types quantities at baseline according to treatment response (responders (CR, PR and SD ≥6 months) versus non-responders (PD and SD <6 months)). Each dot represents a patient. CR, complete response; OPSCC, oropharyngeal squamous cell carcinoma; OS, overall survival; PD, progressive disease; PFS, progression free survival; PR, partial response; SD, stable disease.

**Figure 3**
Gene expression analysis. (A) Gene Set Enrichment Analysis heatmap. Expression data set sort by correlation with treatment response. Criteria is p=0.05, log2 FC ≥1.25 and max intensity 1. Rows represent genes and columns represent samples. Red, upregulated genes; blue, downregulated genes; white, unchanged gene expression. (B) Five most enriched gene sets of non-responders and responders. CR, complete response; GO, Gene Ontology - biological process gene sets from Molecular Signatures Database (MSigDB); HM, hallmark gene sets from Molecular Signatures Database (MSigDB); NES, normalized enrichment score; PD, progressive disease; PR, partial response; SD, stable disease <6 months, SD*, SD ≥6 months.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

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Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials