Clinical Activity of Nivolumab for Human Papilloma Virus-Related Juvenile-Onset Recurrent Respiratory Papillomatosis

Abstract

Background Juvenile‐onset recurrent respiratory papillomatosis (JO‐RRP) is a human papilloma virus‐mediated progressive benign neoplasm that affects children and young adults. Primary management consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO‐RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth. Materials and Methods We treated two patients with refractory JO‐RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling. Results Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on‐treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma. Conclusion Nivolumab appears to have promising activity in JO‐RRP, and further clinical investigation with more patients in clinical trials is warranted. Implications for Practice To the authors' knowledge, this article is the first report describing clinical activity with a programed cell death‐1 (PD‐1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD‐1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.

Reduced NK Cell Cytotoxicity by Papillomatosis-Derived TGF-β Contributing to Low-Risk HPV Persistence in JORRP Patients

“…Juvenile-onset recurrent respiratory papillomatosis (JORRP), primarily caused by low-risk HPV6 and HPV11 infection, is considered as the most common benign laryngeal tumor in children that manifests with hoarseness and loss of voice ( 4 ). Moreover, repeated costly surgical interventions place a lifetime disease burden on families ( 5 , 6 ).…”

Histological Severity Risk Factors Identification in Juvenile-Onset Recurrent Respiratory Papillomatosis: How Immunohistochemistry and AI Algorithms Can Help?

“…Multiple endolaryngeal procedures can lead to glottis synechia and irreversible damage to the vocal cords as well as impaired social life ( 22 ). To improve the surgical outcome and extend symptom-free periods, numerous adjuvant treatments have been tried: interferon α ( 23 ), celecoxib ( 24 ), bevacizumab ( 25 ), cidofovir ( 26 , 27 ), PD-1/PD-L1 immunotherapy ( 28 , 29 ), and the quadrivalent HPV vaccine ( 30 ). At the time of writing, none of these treatments have been recommended for routine use by the International Pediatric Otolaryngology Group ( 31 ).…”

“…At the time of writing, none of these treatments have been recommended for routine use by the International Pediatric Otolaryngology Group ( 31 ). The most promising ones are the quadrivalent HPV vaccine, bevacizumab and PD-1/PD-L1 immunotherapies which appear to decrease relapses ( 28 , 29 , 32 , 33 ).…”

Juvenile-Onset Recurrent Respiratory Papillomatosis Aggressiveness: In Situ Study of the Level of Transcription of HPV E6 and E7

“…Multiple endolaryngeal procedures can lead to glottis synechia and irreversible damage to the vocal cords, as well as an impaired social life [ 23 ]. To improve the surgical outcome and extend the symptom-free interval, numerous adjuvant treatments have been tried: interferon α [ 24 ], celecoxib [ 25 ], bevacizumab [ 26 ], cidofovir [ 27 , 28 ], PD-1/PD-L1 immunotherapy [ 29 , 30 ] and the quadrivalent HPV vaccine [ 31 ]. Currently, routine use of these treatments is not recommended by the International Pediatric Otolaryngology Group [ 32 ].…”

“…Currently, routine use of these treatments is not recommended by the International Pediatric Otolaryngology Group [ 32 ]. The most promising approaches are the quadrivalent HPV vaccine, bevacizumab and PD-1/PD-L1 immunotherapies which appear to decrease relapses [ 29 , 30 , 33 , 34 ]. Systemic bevacizumab, a monoclonal antibody against VEGF-A, seems to be the most promising treatment for aggressive forms of JoRRP, as several studies found a rapid and sustained partial or complete response to treatment in patients with lung involvement [ 35 , 36 ].…”