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

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.

Keywords: Avelumab; Human papillomavirus; Immune checkpoint inhibition; Recurrent respiratory papillomatosis.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the National Cancer Institute (NCI) Institution Review Board and the National Institutes of Health Clinical Center (NCT02859454), and informed consent was obtained from all patients.

Consent for publication

Full consent for the publication of patient demographics and endoscopic images was obtained.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Clinical response following initiation of avelumab in patients with recurrent respiratory papillomatosis. a, A spider plot of change in laryngeal disease burden for each patient, as measured by anatomic Derkay score, is shown. The dotted line shows the time that avelumab was initiated. The negative time points reflect screening assessments prior to starting treatment. Patients 5, 7, 8, 9 and 11 received 6 doses of avelumab over 12 weeks. Patients 1, 2, 3, 4, 6, 10 and 12 received three doses over 6 weeks. b, Representative endoscopic images of RRP lesions for patients 5, 6 and 9 at the timepoints indicated are displayed. c, A spider plot of the change in pulmonary disease burden for each patient, as measured by CT scan imaging per RECIST1.1 guidelines, is shown. d, Representative images from CT scans from patients 6, 10 and 11 are displayed. Red arrows point to index lesions

Fig. 2

Changes in vocal function and surgery-free interval in patients with recurrent respiratory papillomatosis. a, A spider plot of change in VHI-10 scores is shown. b, A swimmer’s plot that demonstrates the frequency of surgical interventions before and after treatment with avelumab is shown. Each patient received a protocol indicated surgical intervention that occurred 6 or 12 weeks after initiation of avelumab at time zero. Yellow regions indicate the administration of a systemic therapy (anti-PD-1 mAb for patient 2, systemic bevacizumab for patients 3 and 4) for some patients after completing the protocol. c, The change in the number of clinically indicated surgical interventions per 12 patient-months before and after completion of the study. P = 0.008 by Wilcoxon matched-pairs analysis

Fig. 3

HPV-specific T-cell responses and viral burden in patients treated with avelumab. a, HPV-specific responses in papilloma-infiltrating T-cells from patients 5 and 9 were measured by interferon gamma enzyme-linked immunospot assays. Antigen presenting cells were loaded with RNA encoding individual transcripts of HPV 6 (patient 5) or HPV 11 (Patient 9) genes. Patients 7 and 8 did not demonstrate HPV-specific responses in papilloma-infiltrating T-cells. b, HPV viral load for HPV 6 (patient 5) or HPV 11 (Patient 9) in papilloma and normal mucosa was determined by quantitative-polymerase chain reaction. c, The Tissue Inflammation Signature was calculated from NanoString IO 360 analysis for patients 5, 7, 8, and 9