Dual PD-L1 and TGF-b blockade in patients with recurrent respiratory papillomatosis
Open accessAbstract
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 alfa 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 alfa in adults with RRP. Papilloma samples before and after treatment with bintrafusp alfa 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 .
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- Authors
- Robbins, Y., Friedman, J., Clavijo, P. E., Sievers, C., Bai, K., Donahue, R. N., Schlom, J., Sinkoe, A., Abdul Sater, H., Gulley, J. L., Norberg, S., Hinrichs, C. S., & Allen, C.
- Affiliations
- National Institutes of Health (US)
- Section on Translational Tumor Immunology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA
- National Cancer Institute (US)
- Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA
- Rutgers Cancer Institute (US)
- Corresponding author
- Allen, Clint
- ORCID
- Venue
- Journal for ImmunoTherapy of Cancer
- Publisher
- BMJ
- Published
- 2021-08
- Volume
- 9
- Issue
- 8
- Pages
- e003113
- ISSN
- 2051-1426 (ISSN-L)
- PMC
- PMC8407210
- OpenAlex
- W3197676689
- Cited by
- 17
- References
- 37
- Citations by year
- 2026: 3 · 2025: 2 · 2023: 6 · 2022: 6
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-10-18)
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Intramural Research Program of the National Institutes of Health
- Center for Cancer Research, National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
- Keywords
- recurrent respiratory papillomatosis, PD-L1 blockade, TGF-beta inhibition, avelumab, human papillomavirus, TGF-beta signaling, Smad3 phosphorylation, p21, Ki-67, head and neck cancer, airway obstruction
- MeSH terms
- Immune Checkpoint Inhibitors, Animals, Antibodies, Monoclonal, Female, Humans, Immunologic Factors, Immunotherapy, Papilloma, Respiratory Tract Infections, Transforming Growth Factor beta, Papillomavirus Infections, NIH 3T3 Cells, Mice, Tumor Microenvironment, Antibodies, Monoclonal, Humanized
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