Safety and clinical activity of PD-L1 blockade in patients with aggressive recurrent respiratory papillomatosis

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Abstract

Background

Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV)-driven disorder that causes substantial morbidity and can lead to fatal distal airway obstruction and post-obstructive pneumonias. Patients require frequent surgical debridement of disease, and no approved systemic adjuvant therapies exist.

Methods

A phase II study was conducted to investigate the clinical activity and safety of programmed death-ligand 1 (PD-L1) blockade with avelumab in patients with RRP.

Results

Twelve patients were treated. All patients with laryngeal RRP displayed improvement in disease burden, and 5 of 9 (56%) displayed partial responses. None of 4 patients with pulmonary RRP displayed a response. Using each patient’s surgical history as their own control, patients required fewer surgical interventions after avelumab treatment ( p = 0.008). A subset of partial responders developed HPV-specific reactivity in papilloma-infiltrating T-cells that correlated with reduced HPV viral load and an increased Tissue Inflammation Signature.

Conclusions

Avelumab demonstrated safety and clinical activity in patients with laryngeal RRP. Further study of immune checkpoint blockade for RRP, possibly with longer treatment duration or in combination with other immunotherapies aimed at activating antiviral immunity, is warranted.

Trial registration

NCT, number NCT02859454, registered August 9, 2016.

Electronic supplementary material

The online version of this article (10.1186/s40425-019-0603-3) contains supplementary material, which is available to authorized users.

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Most cited references 21

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Development and validation of the voice handicap index-10.

Thomas Murry, Nicholas J Osborne, S Lee … (2004)

The objective was to develop an abbreviated voice handicap assessment instrument and compare it with the Voice Handicap Index (VHI). Item analysis of the VHI in individuals without voice disorders and patients with voice disorders and creation and validation of the abbreviated VHI. Clinical consensus review of the VHI items was held to prioritize the clinical value of each of the VHI items (30 items in all). Item analysis of the VHI was performed using the VHI responses of 100 patients with voice problems and 159 control subjects. The 10 most robust VHI items were selected using the item analysis and clinical consensus results to form the Voice Handicap Index-10 (VHI-10). Statistical analysis comparing the validity of the VHI-10 with the VHI was performed with 819 patients representing a wide spectrum of voice disorders. Statistical analysis of the VHI and VHI-10 scores from the study group showed no statistically significant differences between the VHI and the VHI-10. Irrespective of diagnosis, the correlation between the VHI and the VHI-10 was greater than .90 (P = .01). The ratios of the VHI-10 to VHI scores for a variety of voice disorder categories were analyzed and found to be consistently greater than the expected value (33%). This suggests that the VHI-10 may be a more robust instrument than the VHI. The VHI-10 is a powerful representation of the VHI that takes less time for the patient to complete without loss of validity. Thus, the VHI-10 can replace the VHI as an instrument to quantify patients' perception of their voice handicap.

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Exploiting the curative potential of adoptive T-cell therapy for cancer.

Christian Hinrichs, Steven Rosenberg (2014)

Adoptive T-cell therapy (ACT) is a potent and flexible cancer treatment modality that can induce complete, durable regression of certain human malignancies. Long-term follow-up of patients receiving tumor-infiltrating lymphocytes (TILs) for metastatic melanoma reveals a substantial subset that experienced complete, lasting tumor regression - and may be cured. Increasing evidence points to mutated gene products as the primary immunological targets of TILs from melanomas. Recent technological advances permit rapid identification of the neoepitopes resulting from these somatic gene mutations and of T cells with reactivity against these targets. Isolation and adoptive transfer of these T cells may improve TIL therapy for melanoma and permit its broader application to non-melanoma tumors. Extension of ACT to other malignancies may also be possible through antigen receptor gene engineering. Tumor regression has been observed following transfer of T cells engineered to express chimeric antigen receptors against CD19 in B-cell malignancies or a T-cell receptor against NY-ESO-1 in synovial cell sarcoma and melanoma. Herein, we review recent clinical trials of TILs and antigen receptor gene therapy for advanced cancers. We discuss lessons from this experience and consider how they might be applied to realize the full curative potential of ACT.

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Generation of Tumor-Infiltrating Lymphocyte Cultures for Use in Adoptive Transfer Therapy for Melanoma Patients

Jos Even, Mark E Dudley, John Wunderlich … (2003)

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Author and article information

Contributors

Clint T. Allen: 301-827-5620 , clint.allen@nih.gov

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Title: Journal for Immunotherapy of Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-1426

Publication date (Electronic): 3 May 2019

Publication date PMC-release: 3 May 2019

Publication date Collection: 2019

Volume: 7

Electronic Location Identifier: 119

Affiliations

[1 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Translational Tumor Immunology Program, National Institute of Deafness and Other Communication Disorders, , National Institutes of Health, ; 10 Center Drive, Room 7N240C, Bethesda, MD 20892 USA

[2 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, Developmental Therapeutics Branch, , National Cancer Institute, National Institutes of Health, ; Bethesda, USA

[3 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, Experimental Transplantation and Immunology Branch, , National Cancer Institute, National Institutes of Health, ; Bethesda, USA

[4 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, University of California Los Angeles School of Medicine, ; Los Angeles, USA

[5 ]ISNI 0000 0001 2186 0438, GRID grid.411667.3, Georgetown University Medical Center, ; Washington, USA

[6 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, Laboratory of Tumor Immunology and Biology, , National Cancer Institute, National Institutes of Health, ; Bethesda, USA

[7 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, Genitourinary Malignancies Branch, , National Cancer Institute, National Institutes of Health, ; Bethesda, USA

Article

Publisher ID: 603

DOI: 10.1186/s40425-019-0603-3

PMC ID: 6500000

PubMed ID: 31053174

SO-VID: e5762026-cd2e-4ff9-b864-4585d874cf04

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 21 February 2019

Date accepted : 23 April 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000055, National Institute on Deafness and Other Communication Disorders;

Award ID: ZIA-DC000087

Award Recipient : Clint T. Allen

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: Intramural Funding

Award Recipient : Christian S. Hinrichs

Custom metadata

Keywords: immune checkpoint inhibition,avelumab,human papillomavirus,recurrent respiratory papillomatosis

Data availability:

Keywords: immune checkpoint inhibition, avelumab, human papillomavirus, recurrent respiratory papillomatosis

Safety and clinical activity of PD-L1 blockade in patients with aggressive recurrent respiratory papillomatosis

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Abstract

Background

Methods

Results

Conclusions

Trial registration

Electronic supplementary material

Related collections

Fandom activity

Most cited references 21

Development and validation of the voice handicap index-10.

Exploiting the curative potential of adoptive T-cell therapy for cancer.

Generation of Tumor-Infiltrating Lymphocyte Cultures for Use in Adoptive Transfer Therapy for Melanoma Patients

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