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Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination

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Abstract

In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500 μg per peptide dose, the 50 μg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50 % at the 50 μg dose (7 of 14) and 100 μg dose (3 of 6), and 45 % overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in three subjects after vaccination, and the viral loads significantly decreased in nine subjects in whom HPV 16 infection was detected at entry and exit (p = 0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p = 0.02 and 0.0004 after 2 and 4 vaccinations, respectively). T-helper type 2 cells initially increased after two vaccinations (p = 0.01), but decreased below the baseline level after four vaccinations although not significantly. Pre-vaccination regulatory T cell levels were significantly lower in histological responders compared to non-responders (p = 0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened.

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Abbreviations

AE:

Adverse event

β-NGF:

β-Nerve growth factor

CCL7:

Chemokine (C–C motif) ligand 7

CIN:

Cervical intraepithelial neoplasia

CT:

Threshold cycle

CXCL1:

Chemokine (C–X–C motif) ligand 1

CXCL9:

Chemokine (C–X–C motif) ligand 9

FASP:

Filter-aided sample preparation

FGF:

Basic fibroblast growth factor

HGF:

Hepatocyte growth factor

HPV 16:

HPV type 16

HSIL:

High-grade squamous intraepithelial lesion

IL-1RA:

IL-1 receptor agonist

IL-2Rα:

IL-2 receptor α

IP-10:

IFN-γ-induced protein 10

LC–MS/MS:

Liquid chromatography–dual mass spectrometry

MCP-1:

Monocyte chemotactic protein 1

MIF:

Macrophage migration inhibitory factor

NaCl:

Sodium chloride

PDGF-BB:

Platelet-derived growth factor subunit B

RANTES:

Regulated on activation, normal T cell expressed and secreted

SCF:

Stem cell factor

SCGF-β:

Stem cell growth factor β

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This study was supported by a number of grants from National Institutes of Health. “Understanding and Enhancing T-Cell Responses to High Risk Human Papillomaviruses” (R01CA143130) and the Translational Research Institute (UL1TR000039) supported the Phase I clinical trial. The University of Arkansas for Medical Sciences Proteomics Core Laboratory is supported by the Arkansas IDeA Network for Biomedical Research Excellence (P20GM103429), the University of Arkansas Center for Protein Structure and Function (P30GM103450), and the University of Arkansas for Medical Sciences Center for Microbial Pathogenesis and Host Inflammatory Responses (P20GM103625).

Author information

Authors and Affiliations

  1. Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 502, Little Rock, Arkansas, 72205, USA

    Hannah N. Coleman, Alexander Kieber, Charles Matthew Quick & Mayumi Nakagawa

  2. Department of Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    William W. Greenfield & Wilbur. C. Hitt

  3. Translational Research Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    Shawna L. Stratton & Rita Vaughn

  4. Department of Dermatology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    Andrea M. Moerman-Herzog

  5. Department of Biostatistics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    Horace J. Spencer & Stephen W. Erickson

  6. Department of Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    Laura F. Hutchins

  7. Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    Samuel G. Mackintosh & Ricky D. Edmondson

  8. Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    Ricky D. Edmondson

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  1. Hannah N. Coleman
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  2. William W. Greenfield
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  9. Charles Matthew Quick
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  10. Laura F. Hutchins
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  14. Mayumi Nakagawa
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Corresponding author

Correspondence to Mayumi Nakagawa.

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Conflict of interest

Mayumi Nakagawa is one of the inventors named in patents and patent applications describing PepCan. Other authors do not have any conflict of interest to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board, the Food and Drug Administration, and with the 1964 Helsinki Declaration including its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Coleman, H.N., Greenfield, W.W., Stratton, S.L. et al. Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination. Cancer Immunol Immunother 65, 563–573 (2016). https://doi.org/10.1007/s00262-016-1821-x

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  • DOI: https://doi.org/10.1007/s00262-016-1821-x

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