Dual PD-L1 and TGF-b blockade in patients with recurrent respiratory papillomatosis

J Immunother Cancer. 2021 Aug;9(8):e003113. doi: 10.1136/jitc-2021-003113.


Background: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) driven neoplastic disorder of the upper aerodigestive tract that causes significant morbidity and can lead to fatal airway obstruction. Prior clinical study demonstrated clinical benefit with the programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab. Bintrafusp alpha is a bifunctional inhibitor of PD-L1 and transforming growth factor-beta (TGF-b) that has shown clinical activity in several cancer types.

Methods: We conducted a phase II clinical trial evaluating bintrafusp alpha in adults with RRP. Papilloma samples before and after treatment with bintrafusp alpha were assessed for correlates of response with multiplex immunofluorescence as well as immunological and genomic analyses. Post hoc analyses of papilloma samples before and after treatment with avelumab were assessed for comparison.

Results: Dual PD-L1/TGF-b inhibition failed to abrogate papilloma growth in most subjects and increased the frequency of clinically indicated interventions after treatment in four of eight subjects based on each subject's own historical control. TGF-b neutralization consistently decreased pSMAD3 and p21 and increased Ki67 expression within the basal layers of papillomas, indicating that TGF-b restrained proliferation. These alterations were not observed in papillomas treated with PD-L1 blockade alone. Dual PD-L1/TGF-b inhibition did not enhance anti-HPV immunity within papillomas beyond that observed with PD-L1 blockade. Genomic alterations in TGF-b superfamily genes were infrequent in papillomas and normal mucosa but present in a significant fraction of head and neck carcinomas.

Conclusions: Intact TGF-b signaling restrains proliferation within papillomas, and the use of clinical agents that abrogate this pathway should be avoided in patients with RRP.

Trial registration numbers: NCT03707587 and NCT02859454.

Keywords: head and neck neoplasms; immunohistochemistry; immunotherapy; investigational; therapies; tumor microenvironment.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Immunologic Factors / therapeutic use
  • Immunotherapy / methods*
  • Mice
  • NIH 3T3 Cells
  • Papilloma / drug therapy
  • Papillomavirus Infections / drug therapy*
  • Respiratory Tract Infections / drug therapy*
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Tumor Microenvironment / immunology


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Immune Checkpoint Inhibitors
  • Immunologic Factors
  • Transforming Growth Factor beta
  • avelumab

Supplementary concepts

  • Recurrent respiratory papillomatosis

Associated data

  • ClinicalTrials.gov/NCT02859454
  • ClinicalTrials.gov/NCT03707587