TY - JOUR T1 - Dual PD-L1 and TGF-b blockade in patients with recurrent respiratory papillomatosis JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2021-003113 VL - 9 IS - 8 SP - e003113 AU - Yvette Robbins AU - Jay Friedman AU - Paul E Clavijo AU - Cem Sievers AU - Ke Bai AU - Renee N Donahue AU - Jeffrey Schlom AU - Andrew Sinkoe AU - Houssein Abdul Sater AU - James L Gulley AU - Scott Norberg AU - Christian S Hinrichs AU - Clint Allen Y1 - 2021/08/01 UR - http://jitc.bmj.com/content/9/8/e003113.abstract N2 - 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.Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. All experimental data associated with this work is included in the main report and supplements. Whole exome sequencing data from both clinical trials will be deposited in DBGaP according to the protocol data plans. ER -