RARE DISEASE
Recurrent respiratory papillomatosis
Recurrent respiratory papillomatosis
Recurrent respiratory papillomatosis
Drug discovery
11
drugs
With orphan designations
Overview
Recurrent respiratory papillomatosis (RRP) is a rare, HPV-driven disorder (predominantly types 6/11) characterized by recurrent benign papillomas in the upper aerodigestive tract. These lesions cause progressive airway obstruction, dysphonia, and respiratory compromise. The disease follows a chronic, unpredictable course requiring repeated surgical interventions. While histologically benign, 10–55% of cases show dysplasia, with rare malignant transformation risk [1][4][7].
Burden
Morbidity: Patients endure 4–6 annual surgeries (20% require >10), with lifetime tracheostomy risk and vocal dysfunction [1][4][16].
Economic: Initial 2-year costs reach $76,000/patient; total U.S. annual burden exceeds $123M [2][9][16].
Psychosocial: Chronic interventions disrupt education/employment and increase anxiety, particularly with pulmonary spread (9% of cases) [4][12][16].
Therapies
Surgical: Laser/microdebrider resection for airway preservation; office-based KTP/PDL laser use reduces general anesthesia needs [3][5][8].
Adjuvant therapies: Intralesional/systemic bevacizumab, cidofovir, or interferon-alfa for refractory cases [2][3][8][12].
Emerging options: HPV vaccination (Gardasil-9) shows therapeutic benefit in reducing recurrence; INO-3107 vaccine received FDA Breakthrough Therapy designation [1][2][8].
Categories: rare otorhinolaryngological diseases, rare respiratory diseases
Research Papers
752 drug discovery papers about Recurrent respiratory papillomatosis, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
752 drug discovery papers about Recurrent respiratory papillomatosis, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
vaccines
2026-08-26 | Immunologic Response and Clinical Course After Off-label Nonavalent HPV Vaccination in Juvenile-onset Recurrent Respiratory Papillomatosis Patients.
Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare airway disease caused by human papillomavirus (HPV), most commonly HPV6 or HPV11. Affected children often require repeated surgical procedures, and no curative therapy exists. Off-label HPV vaccination has been proposed as an adjunctive treatment, but vaccine-induced immune responses and the relevance of circulating HPV DNA in benign disease remain unclear. We longitudinally evaluated 2 children with JoRRP who received off-label nonavalent HPV vaccination between 2020 and 2025. Serum HPV-specific binding and neutralizing antibodies were measured before vaccination and after the second and third doses using multiplex serology and a pseudovirion-based neutralization assay. During bronchoscopic follow-up, bronchoalveolar lavage fluid and available biopsy samples were analyzed for HPV DNA. In 1 patient, plasma was additionally tested for circulating HPV DNA by digital polymerase chain reaction. Both children had low or undetectable HPV-specific antibodies at baseline. Vaccination induced strong binding and neutralizing antibody responses against vaccine-included HPV types. During post-vaccination follow-up of 12-29 months after completion of the vaccination series, HPV DNA became undetectable in bronchoalveolar lavage samples, and no new papilloma growth was observed after the last post-vaccination intervention. Circulating HPV DNA was not detected at any time point in the patient tested. Nonavalent HPV vaccination induced robust neutralizing antibody responses in children with JoRRP and was temporally associated with clinical stabilization. Larger studies are needed to clarify clinical benefit and biomarker utility.
2026-07-14 | A Comprehensive Overview of Physical and Adjuvant Therapies for Recurrent Respiratory Papillomatosis: Current Evidence and Future Directions.
This article aims to provide a comprehensive overview of the management strategies for recurrent respiratory papillomatosis (RRP), focusing on the evolution from traditional surgical approaches to contemporary precision medicine, and evaluating the efficacy and safety of current physical therapeutic modalities and adjuvant treatments, thereby offering a framework for clinical decision-making. A comprehensive overview. PubMed, Scopus and Web of Science. We conducted a systematic literature search across three databases from 1995 to 2026. Used the following key words: recurrent respiratory papillomatosis(RRP), physical therapeutic modalities, human papillomavirus (HPV), and adjuvant therapies. Data pertaining to study design, participant characteristics, treatment modalities, and outcomes-such as recurrence rate, surgical interval, vocal function, and adverse events-were systematically extracted. Given the clinical and methodological diversity among the studies, a narrative synthesis was adopted to summarize the evidence. Additionally, the quality of evidence was evaluated using the GRADE approach. Of 128 screened abstracts, 95 full-text articles were reviewed. Current evidence demonstrates that various physical therapeutic modalities-such as the precision of carbon dioxide(CO2) laser, the epithelial-sparing potassium titanyl phosphate (KTP) laser, the rapid debulking coblation, and the cryotherapy-effectively manage RRP. Adjuvant drug therapies, including cidofovir, bevacizumab, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, and DNA immunotherapy prolong surgical intervals, while therapeutic HPV vaccination is associated with reduced surgical frequency. The management of recurrent respiratory papillomatosis (RRP) has evolved into a patient-centered, multimodal strategy that prioritizes airway patency, voice preservation, and quality of life. Treatment is personalized based on lesion characteristics, integrating physical therapeutic modalities with targeted adjuvant medical therapies. Future research focuses on therapeutic vaccines and biomarker discovery to advance toward a cure.
2026-04-08 | Rare case of recurrent respiratory papillomatosis with malignant transformation.
Recurrent respiratory papillomatosis is a benign neoplastic growth of the respiratory system, often linked to human papillomavirus types 6 and 11. This case report presents a rare progression to severe airway obstruction and potential malignancy in a 59-year-old male with a history of smoking, hepatitis B carrier status, pulmonary tuberculosis, and a tracheal papilloma. Initially hospitalized for right upper lobe pneumonia, a computed tomography scan revealed a bronchial tumor. Bronchial brushing, washing, and biopsy confirmed squamous cell papilloma. Treatment included bronchoscopy with argon plasma coagulation ablation and debulking surgery for the right upper lobe bronchus and airway tumor; however, recurrence was noted on a follow-up computed tomography scan. Repeat bronchoscopy with argon plasma coagulation ablation confirmed squamous cell papilloma with squamous cell carcinoma in situ. The patient was administered human papillomavirus vaccination to mitigate disease progression and remains under active surveillance. This paper highlights a rare malignant transformation of airway recurrent respiratory papillomatosis.
2025-12-27 | Codon usage bias of low-risk human papillomavirus types 6 and 11.
Low-risk human papillomaviruses HPV-6 and HPV-11 impose a substantial global burden of benign disease. While genomically similar to high-risk HPV types, their codon usage patterns remain uncharacterized. This study systematically deciphers these patterns in HPV-6 and HPV-11. Analysis included 214 HPV-6 and 100 HPV-11 genomes from the NCBI GenBank database. Genomic analysis identified a strong preference for A/U-ending synonymous codons (over 85% of preferred codons) and low GC content at third codon positions (<35%). Relative dinucleotide abundance analysis further revealed underrepresentation of ApA, CpG, and UpC, and overrepresentation of CpA and UpG, which critically shaped synonymous codon selection in both genotypes. While Effective Number of Codons (ENC) values >49 indicated limited overall codon bias, multi-method analyses (Parity Rule 2, ENC-plot, neutrality plot) established natural selection as the dominant evolutionary force over mutational pressure. Despite moderate host adaptation, a strategic mismatch exists between viral codon preferences and human tRNA abundance, potentially moderating translational efficiency to favor immune evasion and persistence. The Relative Codon Deoptimization Index (RCDI) values approaching 2 further support a moderate adaptation to human codon usage patterns. These findings provide crucial insights into the molecular evolution of low-risk HPVs and inform the development of codon-optimized therapeutic strategies, including vaccines targeting pathologies like genital warts and recurrent respiratory papillomatosis.
2025-12-11 | Public health impact and cost-effectiveness of implementing gender-neutral immunization with the nonavalent human papillomavirus vaccine in South Korea.
This study assessed the impact and cost-effectiveness of gender-neutral immunization with the nonavalent human papillomavirus (HPV) vaccine in South Korea. An established dynamic transmission model of HPV epidemiology was adapted to the South Korean population. Vaccinating both girls and boys with the nonavalent HPV vaccine was compared to the currently administered program of vaccinating girls only with the quadrivalent vaccine. Compared to vaccination of girls only with the quadrivalent HPV vaccine, gender-neutral vaccination with the nonavalent HPV vaccine was projected to prevent 1,282,415 cases of cervical intraepithelial neoplasia grade 1 (CIN1), 918,384 cases of CIN2/3, 36,248 cases of cervical cancer, and 9,313 cervical cancer deaths in females over 100 years. Gender-neutral vaccination was projected to reduce HPV-related vaginal, vulvar, anal, and head & neck cancers in females by 4.8-8.2%, in addition to reductions of 14.6% and 15.8% in genital warts and recurrent respiratory papillomatosis, respectively. In males, gender-neutral vaccination was projected to prevent 666,182 cases of genital warts, 7,422 cases of RRP, 995 cases of anal cancer, 2,441 cases of head & neck cancer, and 122 cases of penile cancer. The incremental cost-effectiveness ratio (ICER) was ₩38.9 million per quality-adjusted life year (QALY), which is below the accepted cost-effectiveness threshold in South Korea. These findings suggest that gender-neutral vaccination with the nonavalent HPV vaccine would reduce the public health burden of HPV disease in both females and males in South Korea and would be cost-effective under base case assumptions about vaccine price and coverage of boys.
small molecules
2026-07-20 | Long-term predictors of recurrence in pediatric recurrent respiratory papillomatosis.
To identify predictors of recurrence in pediatric recurrent respiratory papillomatosis (RRP) using a 10-year prospective cohort, evaluating traditional factors (HPV type, lesion characteristics) and novel patient- and disease-specific variables, and their association with Speech-Quality-of-Life (SQOL). We conducted a multicenter, prospective cohort study of 740 patients (629 pediatric, 111 adult) with histologically confirmed RRP from 2014 to 2023 at five high-volume ENT centers in Pakistan. The primary cohort comprised pediatric patients (onset < 18 years); while adult-onset cases were analyzed as a secondary comparative cohort to evaluate pediatric onset as an independent predictor of recurrence. Data included demographics, HPV type (6, 11, 16, 18), lesion number/location, surgery type, adjuvant therapy, tracheostomy history, age at onset, prior surgery intervals, lesion growth rate, socioeconomic status (SES), comorbidities, and immunodeficiency. The primary outcome was time to first recurrence requiring surgical intervention. Patients without recurrence were censored at their last follow-up visit. Time-to-event outcomes were analyzed using Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression adjusting for all covariates. Standardized lesion assessment demonstrated high inter-rater reliability (kappa = 0.78). Recurrence occurred in 65.0% of pediatric patients versus 45.9% of adult-onset patients (p < 0.001)Independent predictors included pediatric onset, HPV types 11, 16, 18, multiple lesions, tracheal involvement, younger age at onset, faster lesion growth, low SES, immunodeficiency, and shorter prior surgery intervals. Adjuvant therapies were associated with reduced recurrence (Cidofovir HR 0.62; Interferon HR 0.66; Bevacizumab HR 0.53). Surgery type did not independently predict recurrence. Median follow-up was 6.8 years. Lower SQOL scores correlated with higher recurrence frequency (Pearson r = - 0.52, p < 0.001). Recurrence in pediatric RRP is multifactorial. Novel predictors-lesion growth rate, SES, and immunodeficiency-enhance risk stratification. Adjuvant therapies show associative benefit, and SQOL correlates with recurrence, highlighting the clinical importance of functional outcomes.
2026-05-01 | C67-21 Recurrent Adult Tracheal Squamous Papilloma Secondary to Childhood HPV Exposure: An Unusual Cause of Dyspnea
Abstract Introduction Recurrent respiratory papillomatosis (RRP) is a rare benigncondition caused by human papilloma virus (HPV) infection, typically subtypes 6and 11. Although more commonly seen in the larynx and presenting duringchildhood, adult presentations involving the trachea are uncommon and can posesignificant diagnostic challenges when symptoms are nonspecific. We present acase of tracheal squamous papilloma manifesting as unexplained dyspnea in anadult patient with remote childhood airway surgery. Case Presentation 34-year-old man with no significant past medical history presentedto pulmonary clinic with progressive shortness of breath. Pulmonary functiontesting demonstrated a restrictive pattern, prompting a high-resolutionchestCT, which unexpectedly revealed a large soft-tissue mass within the proximaltrachea. The patient denied any prior pulmonary disease but, upon detailedquestioning, recalled undergoing multiple airway procedures as a child to“remove something from his windpipe”, which were discontinued afterage18. Flexible bronchoscopy revealed a large, exophytic soft-tissue masspartially obstructing the tracheal lumen. Multiple biopsies were obtained usingforceps and cryotherapy techniques. Pathology demonstrated squamous papilloma,and testing for high-risk HPV was positive. Review of old surgical recordsconfirmed the previous diagnosis of tracheal squamous papillomatosis duringchildhood. The case was discussed at a multidisciplinary tumor board, where theconsensus was to proceed with bronchoscopic removal using photodynamic therapyto achieve airway patency and minimize recurrence risk. Discussion Tracheal involvement in RRP is rare andoften underrecognized, as symptoms such as dyspnea or cough can mimic otherpulmonary or airway disorders. This case highlights how remote childhoodHPVexposure may result in recurrent adult tracheal papillomatosis decades later. The benign nature of squamous papilloma belies its potential for airwayobstruction, recurrent growth, and rarely, malignant transformation. Accuratediagnosis requires a high index of suspicion, particularly in adults withunexplained airway obstruction and a history of childhood airway procedures.Early detection through bronchoscopy and appropriate multidisciplinarymanagement—including surgical removal and adjunctive therapies such asphotodynamic or antiviral treatment—can optimize outcomes and preventrecurrence. This abstract is funded by: N/A
2026-05-01 | C67-22 A 40-year Journey to Remission: Durable Control of Adult-Onset Recurrent Respiratory Papillomatosis With Argon Plasma Coagulation and Cidofovir
Abstract Introduction Recurrent respiratory papillomatosis (RRP) is a rare but relentlessly recurrent airway disease caused by human papillomavirus (HPV), most commonly types 6 and 11. Adult-onset RRP typically follows an indolent yet persistent course, with repeated recurrences leading to airway obstruction and cumulative morbidity. Tracheobronchial involvement occurs in fewer than 5% of cases and often signals an aggressive, treatment-refractory phenotype. Despite decades of evolving endoscopic and adjuvant strategies, true long-term remission is rarely achieved. We present an extraordinary case of multifocal adult-onset RRP spanning over four decades, initially severe enough to prompt consideration for pneumonectomy, that ultimately achieved complete sustained remission following serial argon plasma coagulation (APC) and intralesional cidofovir therapy. Case Presentation A 71-year-old man, former smoker, with severe asthma, COPD, and OSA on CPAP, had a 40-year history of HPV-associated papillomatosis involving the larynx, trachea, and right lung. His disease began in 1979 with recurrent right-sided pneumonias. Bronchoscopy in 1980 revealed a papillomatous lesion in the right mainstem bronchus, and right pneumonectomy was recommended but deferred. CT chest later revealed right lower lobe bronchiectasis and a tracheal defect. Bronchoscopies from 2015 to 2016 (see images) demonstrated diffuse papillomas in the right vocal cord, trachea, and bronchi with severe dynamic collapse. Lesions were repeatedly ablated with APC and treated with intralesional cidofovir. Within three months, only a small residual lesion remained. By 2020, bronchoscopy confirmed complete clearance with no recurrence. The patient remains asymptomatic and recurrence-free to date. Discussion / Learning Points This case illustrates a rare and remarkable outcome in adult-onset RRP, with complete remission after 40 years of recurrent disease. The patient, once considered for pneumonectomy, achieved sustained control through long-term, multidisciplinary management integrating APC and cidofovir. Cidofovir, a nucleotide analogue that inhibits HPV DNA polymerase, has been shown to reduce lesion burden, prolong recurrence-free intervals, and occasionally induce remission with an excellent safety profile when injected locally. This case highlights its potential durability when combined with meticulous endoscopic therapy. Given that RRP is typically marked by relentless recurrence despite aggressive treatment, this sustained remission emphasizes that individualized, multimodal, and persistent management can sometimes overcome even the most refractory forms of this disease, offering hope for long-term control in adult tracheobronchial RRP. This abstract is funded by: None
2026-04-06 | In-Office Management of Eustachian Tube Dysfunction Secondary to Recurrent Respiratory Papillomatosis of the Nasopharynx: A Novel Approach to a Rare Condition.
Recurrent respiratory papillomatosis (RRP) is characterized by benign papillomatous lesions of the respiratory tract, most commonly involving the larynx. Cases of RRP originating solely from the nasopharynx are rarely reported in the literature. To our knowledge, this is the first reported case of nasopharyngeal RRP causing secondary Eustachian tube dysfunction (ETD) managed by office-based laser excision. We describe a 68-year-old male with a history of nasopharyngeal RRP. The papilloma's location resulted in diminished hearing, tinnitus, and an intermittent ear-popping sensation, findings consistent with ETD. Flexible laryngoscopy revealed a papillomatous lesion on the right torus tubarius completely obstructing the Eustachian tube. Office-based flexible laryngoscopy with laser excision was performed without the need for sedation or operating room resources. Following excision, the patient experienced resolution of symptoms. This case demonstrates the feasibility of office-based laser excision for select cases of nasopharyngeal RRP involving the torus tubarius. Compared with operative management, this approach may offer potential advantages, including reduced healthcare costs, avoidance of general anesthesia, and the ability to perform real-time functional assessment. Further study is needed to evaluate the role of office-based techniques in the management of extralaryngeal RRP.
2026-03-18 | Surgical and Voice Outcomes of Office-Based Recurrent Respiratory Papillomatosis Surgery: A Systematic Review.
To investigate the surgical and voice outcomes associated with office-based laryngeal surgery for the treatment of recurrent respiratory papillomatosis (RRP). PubMed, Google Scholar, and Cochrane databases. Two independent investigators search databases for studies reporting surgical or voice quality outcomes of patients treated with office-based surgery for RRP according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Primary outcomes consisted of surgical (safety, patient tolerance, recurrence, complications, number of interventions) and voice quality (subjective, aerodynamic, and acoustic measurements) outcomes. The bias analysis was conducted through the Methodological Index for Non-Randomized Studies (MINORS). Fifteen studies (13 retrospective, 2 prospective) met inclusion criteria, accounting for 357 patients with RRP mainly treated with PDL, KTP, and Blue Laser office-based surgery. Surgical outcomes reported 50% to 95.8% lesion regression rates. The patient tolerance was good, with smokers reporting the low level of tolerance. The cumulative complication rate was low (1.62%). Voice quality assessments demonstrated significant improvements in subjective measures (VHI-10, GRBAS), while there was no study reporting multidimensional voice quality assessments including subjective, perceptual, aerodynamic, and acoustics measurements. Methodological quality of included studies was low-to-moderate (MINORS scores: 5-9), with inconsistent reporting of confounding factors. Office-based laser surgery is a safe and effective treatment for vocal fold RRP, with an effective reduction of disease burden, satisfactory regression, and a moderate rate of subsequent need for OR management. Future studies are needed to investigate the long-term multidimensional voice quality outcomes related to office-based procedures and to compare them with operating room procedures.
proteins
2026-03-24 | Voice disorders in recurrent respiratory papillomatosis
Recurrent respiratory papillomatosis (RRP), also known as laryngeal papillomatosis, is a rare disease caused by the human papillomavirus. This condition is characterized by benign, wart-like lesions that grow throughout the respiratory tract. These growths in the larynx and on the vocal folds can cause changes in voice quality with progressive hoarseness. Aggressive cases also risk airway obstruction with stridor and difficulty breathing. Currently, there is no cure for RRP. The unpredictable course of the disease and proliferation of the lesions can make it difficult to treat. Both adult and pediatric cases often require multiple surgeries to improve voice quality, preserve the airway, and decrease both the burden and spread of the disease. This chapter will discuss the etiology of this chronic disease, the impact of RRP on phonation and voice quality, assessment, and long-term clinical management through surgical and adjuvant treatments.
2026-02-16 | Recurrent respiratory papillomatosis: Recent advances in HPV-6/HPV-11-targeted immunotherapy.
Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 and 11. Juvenile-onset RRP (JoRRP), typically acquired during birth, and adult-onset RRP (AoRRP), commonly associated with sexual transmission, are both predominantly caused by HPV-6, followed by HPV-11. HPV-11 infection, more frequent in children, is associated with more severe disease, increased risk of tracheobronchial and pulmonary spread, and, rarely, RRP-related mortality. Local immune tolerance within the airway mucosa is thought to impair clearance of HPV-6/11-infected cells, resulting in persistent infection and recurrent papilloma growth. Surgical debulking remains the cornerstone of management; however, JoRRP requires substantially more procedures than AoRRP (4-8 vs 1-2 per year), leading to cumulative morbidity, including vocal fold scarring, anterior commissure webbing, glottic or subglottic stenosis, and pulmonary dissemination. Defective innate immune activation and impaired HPV-specific cellular immunity contribute to viral persistence, with the papilloma microenvironment characterized by ineffective antiviral T-cell responses. To reduce surgical burden, immunotherapeutic strategies targeting HPV-6/11 antigens have been developed. Three platforms have advanced into phase 1-2 clinical trials: a gorilla adenoviral vector (gAdeno)-based therapy, a DNA plasmid vaccine, both encoding HPV-6/HPV-11 E6/E7 oncoproteins, and a Modified Vaccinia Ankara (MVA)-based bovine papillomavirus E2 vaccine. These approaches aim to elicit robust E6/E7-specific cellular immunity, particularly CD8+ T-cell responses, to overcome local immune tolerance and eradicate HPV-infected cells. The gAdeno-based therapy is the first FDA-approved immunotherapy for RRP; however, with annual treatment costs exceeding USD 300,000, ensuring equitable access remains a critical challenge.
2026-01-16 | Recurrent Respiratory Papillomatosis Foundation Position Statement on the Management of Adults With RRP.
With regulatory approval of HPV-specific immunotherapy for recurrent respiratory papillomatosis (RRP) and growing experience with systemic bevacizumab, a management algorithm incorporating these medical treatments is warranted. RRP Foundation (RRPF) Key Opinion Leaders offer a proposed management algorithm for adults with RRP considering published literature and commercial drug availability. Preventative HPV vaccination should be considered for all patients. Determination of HPV type and pulmonary imaging are important for contemporary RRP patient care and assist in decision making. Risks and benefits of papilloma debulking as needed versus medical management of RRP must be deliberated on a patient case-by-case basis. HPV-specific immunotherapy that induces an HPV-specific T cell response to target the underlying HPV infection that is the cause of RRP is safe, offers the possibility of durable disease control following a short treatment course and is the recommended first-line medical treatment for patients who wish to avoid the risks of repeat procedural management. Papilloma disease control with systemic bevacizumab, which carries defined risks and must be continued for clinical benefit is the recommended second-line medical treatment for patients who do not achieve a complete response with immunotherapy and wish to continue medical management. For patients who elect to be treated with debulking procedures as needed, use of locally-administered adjuvant should be considered. This proposed management algorithm from the RRPF serves as a contemporary resource and information guide for adult patients with RRP and their physicians considering treatment options.
2025-12-17 | Nationwide Survey on Recurrent Respiratory Papillomatosis in Japan: Analysis of Long-Term Patients.
To investigate the long-term disease status, clinical course, laryngeal distribution, management, and postoperative recurrence of recurrent respiratory papillomatosis (RRP) diagnosed before the first nationwide survey in Japan. As described in our previous report, we conducted a questionnaire-based survey targeting 782 institutions, asking about the presence of RRP patients during the survey period in 2018 and 2019. A detailed questionnaire was subsequently sent to the 196 institutions that reported having at least one patient, inquiring about age, sex, history of recent surgery, Derkay's score, surgical procedures, and postoperative recurrence. The present study analyzed data from patients who had been diagnosed prior to the beginning of the survey period. Data on 318 previously diagnosed patients were collected from 90 institutions. At their first follow-up visit during the survey period, 85 patients (26.7%) had a Derkay's anatomical score of 0. The true vocal folds were the most commonly affected laryngeal subsites. Of the 318 patients, 165 underwent surgery after the first follow-up visit, and recurrence occurred in 106 after this surgery. The 6- and 12-month additional surgery-free rates were 58.9% and 31.8%. These rates were significantly higher in patients who had undergone one or no surgery within a year prior to the first follow-up visit during the survey period than in those who had undergone two or more surgeries (p = 0.01). The present study revealed real-world data suggesting that the number of recent surgeries and Derkay's anatomical score may be associated with the clinical course of previously diagnosed RRP.
2025-11-01 | 1302 Zopapogene imadenovec, a novel HPV-targeted immuno-activator, induces complete and durable responses in recurrent respiratory papillomatosis patients
Background Recurrent respiratory papillomatosis (RRP) is a rare, neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Significant morbidity can occur due to airway obstruction and transformation into malignant cancer can occur. Zopapogene imadenovec (PAPZIMEOSTM) , a novel HPV-Targeted Immuno-Activator, is the first and only FDA-approved treatment for adults with RRP, and set to be the new standard of care treatment.Methods The pivotal trial ( NCT04724980) evaluated safety and efficacy in adult patients with RRP treated with 4 subcutaneous injections of zopapogene imadenovec (5x1011 particle units per injection; n=35). Zopapogene imadenovec was well-tolerated, with no serious adverse events, no grade >2 treatment-related adverse events, and no early treatment discontinuations. Most common adverse events were injection-site reaction, fatigue, chills, fever, and myalgia. Robust efficacy was observed following the treatment, with 51.4% (95% CI: 34.0 to 68.6) of patients achieving a Complete Response (CR), defined as no requirement for interventions in the 12m following treatment and 86% (30/35) of patients experienced a decrease in interventions.Results As of March 20, 2025, median duration of follow-up for all 35 patients was 30.3m (5 – 36). No new safety events were observed during long-term follow-up.Of 18 initial protocol-defined CRs, 15 (83%) remain in CR with median duration of follow-up of 34m (24-36). Median duration of CR has yet to be reached. 58% (95% CI: 39.1 to 75.5; n=31) and 83% (95% CI: 51.6 to 97.9; n=12) of evaluable patients did not require any interventions in year (Y) 2 and Y3 respectively. 90% and 91% of evaluable patients experienced a decrease in the number of interventions in Y2 and Y3 respectively compared to their 12m pre-treatment period.The development of HPV-specific T cell response post treatment assessed via IFN-γ ELISpot assay demonstrated that zopapogene imadenovec treatment stimulates the induction of HPV-specific T-cells and the magnitude of T-cell response was significantly higher in patients achieving CR or Partial Response compared to non-responders (mean fold-change 164.9 vs 5.1, P<0.018).Neutralizing antibody (NAb) titers collected up to 52-weeks post-treatment remained at little to low levels and there was no correlation between NAb incidence or titer and clinical response.Conclusions These data demonstrate that patients treated with zopapogene imadenovec either maintained consistent CRs for up to 3 years or demonstrated a reduction in the need for clinically indicated interventions following recurrence with excellent long-term safety.Ethics Approval The study obtained ethics approval from the NIH Intramural IRB, 6700B Rockledge Drive, Ste. 4300 Bethesda, Maryland USA 20817. The number/ID of the approval(s) are as follows: IRB ID: 21C0013/ MOD002946 IRB ID: 21C0013/ MOD004094 IRB ID: 21C0013/ MOD001703 IRB ID: 21C0013/ MOD002083 IRB ID: 21C0013/ MOD010746 IRB ID: 21C0013/ MOD006823 IRB ID: 21C0013/ MOD002680 IRB ID: All study participants gave informed consent before taking part and were reconsented according to the NIH IRB guidelines.
antibodies
2026-08-17 | Updated Practice Patterns for Adjuvant Treatment of Recurrent Laryngeal Papillomatosis.
Adjuvant medical treatments are used to reduce recurrence rates of recurrent respiratory papillomatosis (RRP). Prior consensus statements on initiation of adjuvants may not reflect current practices, particularly given safety data published in the interval. The objective of this study is to distribute information on current practices in management of RRP, including the use of adjuvant medications, use of surgical modalities and other treatments, monitoring, as well as attitudes and philosophies. Survey study. Email-distributed survey. A survey was distributed to a large group of laryngologists and pediatric otolaryngologists and responses were collected and analyzed. Responses were collected from 86 surgeons, including 71 specific to adult patients and 16 specific to pediatric patients. Laryngologists reported a threshold of 2 surgeries per year to initiate intralesional adjuvant treatments, while pediatric otolaryngologists reported thresholds of 4 surgeries per year for intralesional bevacizumab and 5 surgeries per year for cidofovir. Variable responses between groups were reported for other factors leading to initiation of adjuvants, surgical tools used, practices around HPV vaccination and testing, monitoring, and attitudes and philosophies regarding treatment of RRP. Current practice patterns and attitudes reflect increased comfort with the initiation of adjuvant treatments earlier in the disease course. New medical treatments that promise a shift away from primarily surgical treatment are highly anticipated.
2026-06-02 | Clonal expansion and phenotypic alterations of TCR Vβ3+ T cells in juvenile-onset recurrent respiratory papillomatosis: implications for tumor-associated immunity and chemokine-mediated T-cell trafficking.
Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare, human papillomavirus (HPV)-driven pediatric disease characterized by recurring papillomas in the respiratory tract. The contribution of dysregulated T-cell immunity to disease severity remains poorly understood. This study included 97 JORRP patients and 124 controls. Due to sample limitations, downstream analyses, including flow cytometry, TCR, and RNA sequencing, were performed on distinct patient subsets (detailed in Methods). We identified a selective expansion of TCR Vβ3+ T cells, including expanded TRBV28 clonotypes, in patients with aggressive disease. These T cells exhibited heightened cytotoxicity and activation markers, and were enriched in papilloma tissues. Within the tumor microenvironment, gene expression profiling revealed upregulated chemokine signaling pathways (CCR2/CCL7, CXCR6/CXCL16) and key immunosuppressive markers, including PD-L1 and TGF-β1. Our findings demonstrate a tumor-specific clonal expansion and functional alteration of TCR Vβ3+ T cells in JORRP, suggesting these pathways as preliminary targets for further investigation.IMPORTANCEOur study identifies a disease-specific T-cell signature in juvenile-onset recurrent respiratory papillomatosis (JORRP), marked by the clonal expansion of TCR Vβ3+ T cells with distinct TRBV28-dominant clonotypes. These T cells exhibit heightened cytotoxic potential and activation markers but appear functionally constrained within an immunosuppressive tumor microenvironment. Additionally, we discovered a dysregulated chemokine axis (CCR2/CCL7 and CXCR6/CXCL16), which likely facilitates T-cell recruitment, yet fails to sustain their antiviral activity. These findings provide mechanistic insights into why HPV-driven papillomas persist despite immune infiltration. Importantly, our work suggests that targeting TCR Vβ3+ T-cell responses and modulating key chemokine pathways could offer novel immunotherapeutic strategies to restore immune control and reduce disease recurrence in JORRP patients.
2026-05-01 | C67-20 A Case of Recurrent Respiratory Papillomatosis Treated With Bevacizumab and Nivolumab
Abstract A 24-year-old man was diagnosed at age 4 with recurrent respiratory papillomatosis (RRP), +HPV, low-risk category. He has had repeated laryngeal and tracheal debridement of airway papillomas. He has also had recurrent hemoptysis. Chest imaging has shown multiple solid and cavitating nodules, bronchiectasis, and thin-walled cysts. He was initially treated with 20 cycles of bevacizumab, with a marked improvement in his laryngeal disease. However, his pulmonary disease continued to progress. In May 2020, bevacizumab was discontinued, and he was started on nivolumab based on a published case series in refractory RRP. Although there was radiologic evidence of improvement in his pulmonary disease, his laryngeal papillomatosis worsened over 4 months of nivolumab therapy. In September 2020, in an effort to control both his pulmonary and upper airway disease, the patient was started on combination therapy with nivolumab and bevacizumab every 3 weeks. His disease remained stable for almost 2 years, until he was hospitalized for an intracranial abscess. His RRP treatment was held for several months. In February 2023, he was admitted for hemoptysis and ultimately underwent lobectomy for a cavitating lesion in the RLL. He remained off any therapy for over a year with close surveillance. During this period, he had increased growth of his laryngeal papillomas and was restarted on bevacizumab. Once again, his upper airway disease responded well, but he had progression of his pulmonary disease. He is currently on bevacizumab and nivolumab every 2 weeks. His laryngeal disease remains under control, with a mixed response in his chest. RRP is a disease caused by chronic infection of HPV-6 and HPV-11 with predilection for the respiratory epithelium. In the 8.9% of RRP patients with pulmonary involvement, there is a significant increase in morbidity as well as lifetime risk of malignant transformation. Small trials have shown positive results with bevacizumab therapy in patients with RRP, including those with pulmonary involvement. However, there are no available systemic treatments for refractory disease. A previous case series of 2 patients with refractory RRP demonstrated some clinical benefit of nivolumab. The decision to trial combination therapy with a VEGF inhibitor and PD-1 blocker in this patient was based on a Phase II trial suggesting clinical efficacy in relapsed ovarian cancer. To our knowledge, this is the first report of combined bevacizumab and nivolumab for RRP. While this patient’s pulmonary disease showed some response to therapy, clearly, more clinical trials are needed. This abstract is funded by: None
2025-10-07 | Prolonged Treatment Gaps and Recurrence Patterns in Recurrent Respiratory Papillomatosis.
Recurrent respiratory papillomatosis (RRP) is characterized by an irregular disease course, with recurrences after long periods of remission. New immunologic strategies are under investigation that aim to eliminate the chronic HPV infection. We evaluated recurrence patterns in RRP patients and sought to identify variables associated with prolonged remission periods. Charts of all RRP patients seen since 2003 at our institution were reviewed. Surgical history and disease status in treatment-free intervals were evaluated. Patient and disease characteristics were compared using chi-squared and Fisher's exact tests in an exploratory analysis. Of 312 RRP patients, 71 (22.8%) experienced a treatment gap (TG) of at least 4 years between treatment and recurrence, with 43 (13.8%) having a TG over 10 years. TG patients did not differ from the remaining cohort in sex, juvenile/adult onset, or other clinical characteristics. To control for the possibility that TG patients resembled the entire cohort because of untreated occult disease, a subset was identified with prolonged (≥ 4 years) definitive remission. Compared to this remission group, TG patients were more likely to undergo surgery rather than office procedures before the gap in treatment (100% vs. 71.4% p = 0.003) and less likely to have supraglottic disease (17.5% vs. 57.1% p = 0.012). Other patient characteristics showed no significant differences. A substantial portion of RRP patients experience recurrence after prolonged treatment-free intervals, and this cohort cannot be easily predicted from available clinical characteristics. This highlights the need for effective immunologic strategies to eliminate the causative chronic infection.
2025-07-11 | Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis.
Human papillomavirus-mediated recurrent respiratory papillomatosis (RRP) is a premalignant neoplasia of the upper airway characterized by significant dysphonia and respiratory obstruction. Immune checkpoint blockade has emerged as a potential alternative to repeated surgical interventions in RRP. Here, we investigated the intralesional T-cell composition and expression of the immune checkpoints programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) in RRP. We analyzed tissue samples from 30 patients treated at a tertiary care center between 2009 and 2021, including paired samples from individual patients collected at different time points. Immunohistochemical staining was performed for CD4, CD8, CTLA-4, FoxP3, and PD-L1 and correlated with disease severity and previous adjuvant therapies. Overall disease burden and intervention-free survival were not associated with the abundance of CD4+, CD8+, or FoxP3+ T cells, nor with immune checkpoint expression. However, patients with aggressive disease exhibited a higher intralesional FoxP3/CD4 T-cell ratio. Prior intralesional cidofovir treatment was associated with reduced CD4+ T-cell infiltration. These findings suggest that a locally immunosuppressive microenvironment, reflected by an elevated FoxP3/CD4 ratio, contributes to disease severity in RRP. Consistent CTLA-4 expression across all evaluated samples supports further investigation of anti-CTLA-4 therapy, either alone or in combination with other checkpoint inhibitors.
other
2026-07-28 | Combined Analysis of scRNA-seq and Bulk RNA-seq Sequencing Revealing the Heterogeneity of Recurrent Respiratory Papillomatosis and Key Molecular Mechanisms of Its Occurrence and Development.
Recurrent respiratory papillomatosis (RRP) is a benign tumor that is highly prone to recurrence and has the potential to become malignant, caused by human papillomavirus (HPV) infection. The underlying mechanism is unclear, and new targets need to be explored urgently. This study integrated single-cell and bulk RNA-seq data, screened key genes through cell communication, machine learning, and animal models, constructed a predictive model, and completed drug prediction and independent validation. This single-cell sequencing study revealed an active fibroblast-epithelial dialogue within the RRP, and defined three subtypes of fibroblasts and their developmental trajectories. It identified key genes such as GJB2 and the ceRNA regulatory network, revealed imbalances in the immune microenvironment, and predicted potential therapeutic drugs. The key genes identified in this study, GJB2, IL36G, and S100A7, can serve as potential molecular markers and therapeutic targets for the early diagnosis, prognosis assessment, and precise treatment of RRP.
2026-07-09 | Zopapogene imadenovec-drba, a novel adenovector-based immunotherapy, induces complete and durable responses in recurrent respiratory papillomatosis
Robustefficacy was observedfollowing zopa treatment with 51% (34 to 69; 95% CI) of patients achieving a complete response (CR), defined as no requirement for interventions in the 12m following treatment.Here we present data up to 51m of followup. ResultsAs of December 15, 2025, with a median duration of follow-up of 36m (range: 30-51m), 83% (15/18) of patients who achieved a CR at 12m remainin CR with no recurrence of papilloma requiring surgicalor medical intervention.Out of the 15 patientsremaining in CR, 3 patients have reached 4 years of follow-up.No new safety events were observed during long-term follow-up. ConclusionsZopa treatment demonstrated significant clinicalbenefit with the vast majorityof CR patients experiencing ongoing durable complete responses for up to 4 years with excellent long-term safety.Updatedfollow-up results for all patientsachieving CR will be available at the time of presentation.
2026-05-27 | Zopapogene imadenovec-drba, a novel non-replicating adenoviral vector-based immunotherapy: Effects on complete and durable responses in recurrent respiratory papillomatosis pivotal trial.
6104 Background: Recurrent respiratory papillomatosis (RRP) is a rare, neoplastic disorder caused by chronic human papillomavirus (HPV) type 6 or 11 infection. Significant morbidity can occur due to airway obstruction and transformation into malignant cancer. Repeat surgical debulking has historically been the most common treatment for RRP symptom management. Zopapogene imadenovec-drba (zopa), a novel adenoviral vector-based immunotherapy, is the first and only FDA-approved treatment for adults with RRP. Zopa is now recommended as the first-line treatment for adults with RRP in an RRP Foundation position statement authored by 16 key opinion leaders (Best et al. Laryngoscope 2026). Methods: The pivotal trial (NCT04724980) evaluated zopa in patients with RRP requiring ≥3 clinically indicated interventions 12 months (m) prior to treatment. 12m follow-up data was reported and demonstrated that 4 subcutaneous injections of zopa (5x10 11 particle units per injection; n=35) were well-tolerated, with no serious adverse events, no grade >2 treatment-related adverse events, and no early treatment discontinuations. The most common adverse events were injection-site reaction, fatigue, chills, fever, and myalgia. Robust efficacy was observed following zopa treatment with 51% (34 to 69; 95% CI) of patients achieving a complete response (CR), defined as no requirement for interventions in the 12m following treatment, and 86% (30/35) of patients experiencing a decrease in interventions in the year following treatment as compared to the year prior to treatment. Here we present data up to 51m of follow-up. Results: As of December 15, 2025, 83% (15/18) of patients who achieved a CR at 12m remain in CR with no recurrence of papilloma requiring surgical or medical intervention. The median duration of follow-up for patients in CR was 36m (range: 30-51m), with 3 patients having a response lasting more than 4 years. No new safety events were observed during long-term follow-up. Conclusions: Zopa treatment demonstrated significant clinical benefit with the vast majority of CR patients experiencing ongoing durable complete responses for up to 4 years with excellent long-term safety. Updated follow-up results for all patients achieving CR will be available at the time of presentation. Clinical trial information: NCT04724980 .
2026-05-09 | The Efficacy and Safety of Systemic Treatment for Managing Recurrent Respiratory Papillomatosis: A Systematic Review and Meta-analysis.
Surgical treatment remains the cornerstone of recurrent respiratory papillomatosis (RRP) management; however, aggressive disease often requires frequent procedures with cumulative morbidity. Contemporary systemic options now include systemic bevacizumab and human papillomavirus (HPV)-specific immunotherapies, with immune checkpoint inhibition under investigation. We systematically reviewed the efficacy and safety of systemic therapies for juvenile- and adult-onset RRP, emphasizing current clinician-relevant treatment options. We comprehensively searched PubMed, Scopus, Web of Science, and the Cochrane Library from inception until January 2026. The included studies evaluated any available systemic treatment for managing adult or juvenile-onset RRP. The main outcomes were complete remission, partial response, and adverse events. All the data analyses were performed using STATA 18 BE. We included 35 studies comprising 925 patients. In juvenile-onset RRP, pooled complete remission with systemic bevacizumab was 60% (95% CI 34-87%), and pooled partial response was 46% (95% CI 21-71%). In adult-onset RRP, pooled complete remission with systemic bevacizumab was 44% (95% CI 26-62%), and pooled partial response was 61% (95% CI 43-79%). The most frequently reported bevacizumab adverse events were hypertension (40%), proteinuria (26%), and epistaxis (22%). HPV-specific immunotherapies (including FDA-approved zopapogene imadenovec-drba [Papzimeos; PRGN-2012] for adults and investigational INO-3107) and PD-1/PD-L1-directed therapies demonstrated encouraging early-phase activity but were too heterogeneous for quantitative pooling. Systemic bevacizumab remains the most mature systemic option with consistent real-world evidence and published dosing guidance. HPV-specific immunotherapy has recently transformed adult RRP management with an FDA-approved, short-course treatment option; ongoing studies will clarify optimal sequencing with bevacizumab and the role of checkpoint inhibition.
2025-12-01 | Modeling and Exploring Recurrent Respiratory Papillomatosis with 3D Cell Cultures
Recurrent respiratory papillomatosis (RRP) is a benign but potentially life-threatening tumor of the airway epithelium that is caused by persistent infection with low-risk human papillomavirus (LR-HPV) type 6 or 11. Current management relies on repeated surgical removal of lesions, as no curative antiviral therapy is available, imposing substantial physical and psychological burden on patients. To develop novel therapeutic strategies, it is essential to elucidate the mechanisms by which LR-HPVs persist, replicate, and drive tumor formation. However, the lack of in vitro models that recapitulate the viral life cycle has hindered its progress. In this study, we established primary epithelial cell cultures from surgical RRP specimens using conditional reprogramming (CR) with J2 feeder fibroblasts and a ROCK inhibitor, achieving a high success rate (～90%). These cells retained LR-HPV genomes and were adaptable to three-dimensional (3D) culture, forming spheroid structures that mimicked in vivo tissue architecture and preserved proliferative and undifferentiated phenotypes. Immunostaining and molecular analyses revealed suppressed cGAS-STING pathway activity and reduced type I interferon response in RRP-derived cells, suggesting impaired innate immune surveillance. This 3D CR-based model provides a robust platform for investigating the pathogenesis of LR-HPV and host–virus interactions, potentially accelerating the development of targeted therapies for RRP.
vaccines
2026-08-26 | Immunologic Response and Clinical Course After Off-label Nonavalent HPV Vaccination in Juvenile-onset Recurrent Respiratory Papillomatosis Patients.
Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare airway disease caused by human papillomavirus (HPV), most commonly HPV6 or HPV11. Affected children often require repeated surgical procedures, and no curative therapy exists. Off-label HPV vaccination has been proposed as an adjunctive treatment, but vaccine-induced immune responses and the relevance of circulating HPV DNA in benign disease remain unclear. We longitudinally evaluated 2 children with JoRRP who received off-label nonavalent HPV vaccination between 2020 and 2025. Serum HPV-specific binding and neutralizing antibodies were measured before vaccination and after the second and third doses using multiplex serology and a pseudovirion-based neutralization assay. During bronchoscopic follow-up, bronchoalveolar lavage fluid and available biopsy samples were analyzed for HPV DNA. In 1 patient, plasma was additionally tested for circulating HPV DNA by digital polymerase chain reaction. Both children had low or undetectable HPV-specific antibodies at baseline. Vaccination induced strong binding and neutralizing antibody responses against vaccine-included HPV types. During post-vaccination follow-up of 12-29 months after completion of the vaccination series, HPV DNA became undetectable in bronchoalveolar lavage samples, and no new papilloma growth was observed after the last post-vaccination intervention. Circulating HPV DNA was not detected at any time point in the patient tested. Nonavalent HPV vaccination induced robust neutralizing antibody responses in children with JoRRP and was temporally associated with clinical stabilization. Larger studies are needed to clarify clinical benefit and biomarker utility.
2026-07-14 | A Comprehensive Overview of Physical and Adjuvant Therapies for Recurrent Respiratory Papillomatosis: Current Evidence and Future Directions.
This article aims to provide a comprehensive overview of the management strategies for recurrent respiratory papillomatosis (RRP), focusing on the evolution from traditional surgical approaches to contemporary precision medicine, and evaluating the efficacy and safety of current physical therapeutic modalities and adjuvant treatments, thereby offering a framework for clinical decision-making. A comprehensive overview. PubMed, Scopus and Web of Science. We conducted a systematic literature search across three databases from 1995 to 2026. Used the following key words: recurrent respiratory papillomatosis(RRP), physical therapeutic modalities, human papillomavirus (HPV), and adjuvant therapies. Data pertaining to study design, participant characteristics, treatment modalities, and outcomes-such as recurrence rate, surgical interval, vocal function, and adverse events-were systematically extracted. Given the clinical and methodological diversity among the studies, a narrative synthesis was adopted to summarize the evidence. Additionally, the quality of evidence was evaluated using the GRADE approach. Of 128 screened abstracts, 95 full-text articles were reviewed. Current evidence demonstrates that various physical therapeutic modalities-such as the precision of carbon dioxide(CO2) laser, the epithelial-sparing potassium titanyl phosphate (KTP) laser, the rapid debulking coblation, and the cryotherapy-effectively manage RRP. Adjuvant drug therapies, including cidofovir, bevacizumab, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, and DNA immunotherapy prolong surgical intervals, while therapeutic HPV vaccination is associated with reduced surgical frequency. The management of recurrent respiratory papillomatosis (RRP) has evolved into a patient-centered, multimodal strategy that prioritizes airway patency, voice preservation, and quality of life. Treatment is personalized based on lesion characteristics, integrating physical therapeutic modalities with targeted adjuvant medical therapies. Future research focuses on therapeutic vaccines and biomarker discovery to advance toward a cure.
2026-04-08 | Rare case of recurrent respiratory papillomatosis with malignant transformation.
Recurrent respiratory papillomatosis is a benign neoplastic growth of the respiratory system, often linked to human papillomavirus types 6 and 11. This case report presents a rare progression to severe airway obstruction and potential malignancy in a 59-year-old male with a history of smoking, hepatitis B carrier status, pulmonary tuberculosis, and a tracheal papilloma. Initially hospitalized for right upper lobe pneumonia, a computed tomography scan revealed a bronchial tumor. Bronchial brushing, washing, and biopsy confirmed squamous cell papilloma. Treatment included bronchoscopy with argon plasma coagulation ablation and debulking surgery for the right upper lobe bronchus and airway tumor; however, recurrence was noted on a follow-up computed tomography scan. Repeat bronchoscopy with argon plasma coagulation ablation confirmed squamous cell papilloma with squamous cell carcinoma in situ. The patient was administered human papillomavirus vaccination to mitigate disease progression and remains under active surveillance. This paper highlights a rare malignant transformation of airway recurrent respiratory papillomatosis.
2025-12-27 | Codon usage bias of low-risk human papillomavirus types 6 and 11.
Low-risk human papillomaviruses HPV-6 and HPV-11 impose a substantial global burden of benign disease. While genomically similar to high-risk HPV types, their codon usage patterns remain uncharacterized. This study systematically deciphers these patterns in HPV-6 and HPV-11. Analysis included 214 HPV-6 and 100 HPV-11 genomes from the NCBI GenBank database. Genomic analysis identified a strong preference for A/U-ending synonymous codons (over 85% of preferred codons) and low GC content at third codon positions (<35%). Relative dinucleotide abundance analysis further revealed underrepresentation of ApA, CpG, and UpC, and overrepresentation of CpA and UpG, which critically shaped synonymous codon selection in both genotypes. While Effective Number of Codons (ENC) values >49 indicated limited overall codon bias, multi-method analyses (Parity Rule 2, ENC-plot, neutrality plot) established natural selection as the dominant evolutionary force over mutational pressure. Despite moderate host adaptation, a strategic mismatch exists between viral codon preferences and human tRNA abundance, potentially moderating translational efficiency to favor immune evasion and persistence. The Relative Codon Deoptimization Index (RCDI) values approaching 2 further support a moderate adaptation to human codon usage patterns. These findings provide crucial insights into the molecular evolution of low-risk HPVs and inform the development of codon-optimized therapeutic strategies, including vaccines targeting pathologies like genital warts and recurrent respiratory papillomatosis.
2025-12-11 | Public health impact and cost-effectiveness of implementing gender-neutral immunization with the nonavalent human papillomavirus vaccine in South Korea.
This study assessed the impact and cost-effectiveness of gender-neutral immunization with the nonavalent human papillomavirus (HPV) vaccine in South Korea. An established dynamic transmission model of HPV epidemiology was adapted to the South Korean population. Vaccinating both girls and boys with the nonavalent HPV vaccine was compared to the currently administered program of vaccinating girls only with the quadrivalent vaccine. Compared to vaccination of girls only with the quadrivalent HPV vaccine, gender-neutral vaccination with the nonavalent HPV vaccine was projected to prevent 1,282,415 cases of cervical intraepithelial neoplasia grade 1 (CIN1), 918,384 cases of CIN2/3, 36,248 cases of cervical cancer, and 9,313 cervical cancer deaths in females over 100 years. Gender-neutral vaccination was projected to reduce HPV-related vaginal, vulvar, anal, and head & neck cancers in females by 4.8-8.2%, in addition to reductions of 14.6% and 15.8% in genital warts and recurrent respiratory papillomatosis, respectively. In males, gender-neutral vaccination was projected to prevent 666,182 cases of genital warts, 7,422 cases of RRP, 995 cases of anal cancer, 2,441 cases of head & neck cancer, and 122 cases of penile cancer. The incremental cost-effectiveness ratio (ICER) was ₩38.9 million per quality-adjusted life year (QALY), which is below the accepted cost-effectiveness threshold in South Korea. These findings suggest that gender-neutral vaccination with the nonavalent HPV vaccine would reduce the public health burden of HPV disease in both females and males in South Korea and would be cost-effective under base case assumptions about vaccine price and coverage of boys.
small molecules
2026-07-20 | Long-term predictors of recurrence in pediatric recurrent respiratory papillomatosis.
To identify predictors of recurrence in pediatric recurrent respiratory papillomatosis (RRP) using a 10-year prospective cohort, evaluating traditional factors (HPV type, lesion characteristics) and novel patient- and disease-specific variables, and their association with Speech-Quality-of-Life (SQOL). We conducted a multicenter, prospective cohort study of 740 patients (629 pediatric, 111 adult) with histologically confirmed RRP from 2014 to 2023 at five high-volume ENT centers in Pakistan. The primary cohort comprised pediatric patients (onset < 18 years); while adult-onset cases were analyzed as a secondary comparative cohort to evaluate pediatric onset as an independent predictor of recurrence. Data included demographics, HPV type (6, 11, 16, 18), lesion number/location, surgery type, adjuvant therapy, tracheostomy history, age at onset, prior surgery intervals, lesion growth rate, socioeconomic status (SES), comorbidities, and immunodeficiency. The primary outcome was time to first recurrence requiring surgical intervention. Patients without recurrence were censored at their last follow-up visit. Time-to-event outcomes were analyzed using Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression adjusting for all covariates. Standardized lesion assessment demonstrated high inter-rater reliability (kappa = 0.78). Recurrence occurred in 65.0% of pediatric patients versus 45.9% of adult-onset patients (p < 0.001)Independent predictors included pediatric onset, HPV types 11, 16, 18, multiple lesions, tracheal involvement, younger age at onset, faster lesion growth, low SES, immunodeficiency, and shorter prior surgery intervals. Adjuvant therapies were associated with reduced recurrence (Cidofovir HR 0.62; Interferon HR 0.66; Bevacizumab HR 0.53). Surgery type did not independently predict recurrence. Median follow-up was 6.8 years. Lower SQOL scores correlated with higher recurrence frequency (Pearson r = - 0.52, p < 0.001). Recurrence in pediatric RRP is multifactorial. Novel predictors-lesion growth rate, SES, and immunodeficiency-enhance risk stratification. Adjuvant therapies show associative benefit, and SQOL correlates with recurrence, highlighting the clinical importance of functional outcomes.
2026-05-01 | C67-21 Recurrent Adult Tracheal Squamous Papilloma Secondary to Childhood HPV Exposure: An Unusual Cause of Dyspnea
Abstract Introduction Recurrent respiratory papillomatosis (RRP) is a rare benigncondition caused by human papilloma virus (HPV) infection, typically subtypes 6and 11. Although more commonly seen in the larynx and presenting duringchildhood, adult presentations involving the trachea are uncommon and can posesignificant diagnostic challenges when symptoms are nonspecific. We present acase of tracheal squamous papilloma manifesting as unexplained dyspnea in anadult patient with remote childhood airway surgery. Case Presentation 34-year-old man with no significant past medical history presentedto pulmonary clinic with progressive shortness of breath. Pulmonary functiontesting demonstrated a restrictive pattern, prompting a high-resolutionchestCT, which unexpectedly revealed a large soft-tissue mass within the proximaltrachea. The patient denied any prior pulmonary disease but, upon detailedquestioning, recalled undergoing multiple airway procedures as a child to“remove something from his windpipe”, which were discontinued afterage18. Flexible bronchoscopy revealed a large, exophytic soft-tissue masspartially obstructing the tracheal lumen. Multiple biopsies were obtained usingforceps and cryotherapy techniques. Pathology demonstrated squamous papilloma,and testing for high-risk HPV was positive. Review of old surgical recordsconfirmed the previous diagnosis of tracheal squamous papillomatosis duringchildhood. The case was discussed at a multidisciplinary tumor board, where theconsensus was to proceed with bronchoscopic removal using photodynamic therapyto achieve airway patency and minimize recurrence risk. Discussion Tracheal involvement in RRP is rare andoften underrecognized, as symptoms such as dyspnea or cough can mimic otherpulmonary or airway disorders. This case highlights how remote childhoodHPVexposure may result in recurrent adult tracheal papillomatosis decades later. The benign nature of squamous papilloma belies its potential for airwayobstruction, recurrent growth, and rarely, malignant transformation. Accuratediagnosis requires a high index of suspicion, particularly in adults withunexplained airway obstruction and a history of childhood airway procedures.Early detection through bronchoscopy and appropriate multidisciplinarymanagement—including surgical removal and adjunctive therapies such asphotodynamic or antiviral treatment—can optimize outcomes and preventrecurrence. This abstract is funded by: N/A
2026-05-01 | C67-22 A 40-year Journey to Remission: Durable Control of Adult-Onset Recurrent Respiratory Papillomatosis With Argon Plasma Coagulation and Cidofovir
Abstract Introduction Recurrent respiratory papillomatosis (RRP) is a rare but relentlessly recurrent airway disease caused by human papillomavirus (HPV), most commonly types 6 and 11. Adult-onset RRP typically follows an indolent yet persistent course, with repeated recurrences leading to airway obstruction and cumulative morbidity. Tracheobronchial involvement occurs in fewer than 5% of cases and often signals an aggressive, treatment-refractory phenotype. Despite decades of evolving endoscopic and adjuvant strategies, true long-term remission is rarely achieved. We present an extraordinary case of multifocal adult-onset RRP spanning over four decades, initially severe enough to prompt consideration for pneumonectomy, that ultimately achieved complete sustained remission following serial argon plasma coagulation (APC) and intralesional cidofovir therapy. Case Presentation A 71-year-old man, former smoker, with severe asthma, COPD, and OSA on CPAP, had a 40-year history of HPV-associated papillomatosis involving the larynx, trachea, and right lung. His disease began in 1979 with recurrent right-sided pneumonias. Bronchoscopy in 1980 revealed a papillomatous lesion in the right mainstem bronchus, and right pneumonectomy was recommended but deferred. CT chest later revealed right lower lobe bronchiectasis and a tracheal defect. Bronchoscopies from 2015 to 2016 (see images) demonstrated diffuse papillomas in the right vocal cord, trachea, and bronchi with severe dynamic collapse. Lesions were repeatedly ablated with APC and treated with intralesional cidofovir. Within three months, only a small residual lesion remained. By 2020, bronchoscopy confirmed complete clearance with no recurrence. The patient remains asymptomatic and recurrence-free to date. Discussion / Learning Points This case illustrates a rare and remarkable outcome in adult-onset RRP, with complete remission after 40 years of recurrent disease. The patient, once considered for pneumonectomy, achieved sustained control through long-term, multidisciplinary management integrating APC and cidofovir. Cidofovir, a nucleotide analogue that inhibits HPV DNA polymerase, has been shown to reduce lesion burden, prolong recurrence-free intervals, and occasionally induce remission with an excellent safety profile when injected locally. This case highlights its potential durability when combined with meticulous endoscopic therapy. Given that RRP is typically marked by relentless recurrence despite aggressive treatment, this sustained remission emphasizes that individualized, multimodal, and persistent management can sometimes overcome even the most refractory forms of this disease, offering hope for long-term control in adult tracheobronchial RRP. This abstract is funded by: None
2026-04-06 | In-Office Management of Eustachian Tube Dysfunction Secondary to Recurrent Respiratory Papillomatosis of the Nasopharynx: A Novel Approach to a Rare Condition.
Recurrent respiratory papillomatosis (RRP) is characterized by benign papillomatous lesions of the respiratory tract, most commonly involving the larynx. Cases of RRP originating solely from the nasopharynx are rarely reported in the literature. To our knowledge, this is the first reported case of nasopharyngeal RRP causing secondary Eustachian tube dysfunction (ETD) managed by office-based laser excision. We describe a 68-year-old male with a history of nasopharyngeal RRP. The papilloma's location resulted in diminished hearing, tinnitus, and an intermittent ear-popping sensation, findings consistent with ETD. Flexible laryngoscopy revealed a papillomatous lesion on the right torus tubarius completely obstructing the Eustachian tube. Office-based flexible laryngoscopy with laser excision was performed without the need for sedation or operating room resources. Following excision, the patient experienced resolution of symptoms. This case demonstrates the feasibility of office-based laser excision for select cases of nasopharyngeal RRP involving the torus tubarius. Compared with operative management, this approach may offer potential advantages, including reduced healthcare costs, avoidance of general anesthesia, and the ability to perform real-time functional assessment. Further study is needed to evaluate the role of office-based techniques in the management of extralaryngeal RRP.
2026-03-18 | Surgical and Voice Outcomes of Office-Based Recurrent Respiratory Papillomatosis Surgery: A Systematic Review.
To investigate the surgical and voice outcomes associated with office-based laryngeal surgery for the treatment of recurrent respiratory papillomatosis (RRP). PubMed, Google Scholar, and Cochrane databases. Two independent investigators search databases for studies reporting surgical or voice quality outcomes of patients treated with office-based surgery for RRP according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Primary outcomes consisted of surgical (safety, patient tolerance, recurrence, complications, number of interventions) and voice quality (subjective, aerodynamic, and acoustic measurements) outcomes. The bias analysis was conducted through the Methodological Index for Non-Randomized Studies (MINORS). Fifteen studies (13 retrospective, 2 prospective) met inclusion criteria, accounting for 357 patients with RRP mainly treated with PDL, KTP, and Blue Laser office-based surgery. Surgical outcomes reported 50% to 95.8% lesion regression rates. The patient tolerance was good, with smokers reporting the low level of tolerance. The cumulative complication rate was low (1.62%). Voice quality assessments demonstrated significant improvements in subjective measures (VHI-10, GRBAS), while there was no study reporting multidimensional voice quality assessments including subjective, perceptual, aerodynamic, and acoustics measurements. Methodological quality of included studies was low-to-moderate (MINORS scores: 5-9), with inconsistent reporting of confounding factors. Office-based laser surgery is a safe and effective treatment for vocal fold RRP, with an effective reduction of disease burden, satisfactory regression, and a moderate rate of subsequent need for OR management. Future studies are needed to investigate the long-term multidimensional voice quality outcomes related to office-based procedures and to compare them with operating room procedures.
proteins
2026-03-24 | Voice disorders in recurrent respiratory papillomatosis
Recurrent respiratory papillomatosis (RRP), also known as laryngeal papillomatosis, is a rare disease caused by the human papillomavirus. This condition is characterized by benign, wart-like lesions that grow throughout the respiratory tract. These growths in the larynx and on the vocal folds can cause changes in voice quality with progressive hoarseness. Aggressive cases also risk airway obstruction with stridor and difficulty breathing. Currently, there is no cure for RRP. The unpredictable course of the disease and proliferation of the lesions can make it difficult to treat. Both adult and pediatric cases often require multiple surgeries to improve voice quality, preserve the airway, and decrease both the burden and spread of the disease. This chapter will discuss the etiology of this chronic disease, the impact of RRP on phonation and voice quality, assessment, and long-term clinical management through surgical and adjuvant treatments.
2026-02-16 | Recurrent respiratory papillomatosis: Recent advances in HPV-6/HPV-11-targeted immunotherapy.
Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 and 11. Juvenile-onset RRP (JoRRP), typically acquired during birth, and adult-onset RRP (AoRRP), commonly associated with sexual transmission, are both predominantly caused by HPV-6, followed by HPV-11. HPV-11 infection, more frequent in children, is associated with more severe disease, increased risk of tracheobronchial and pulmonary spread, and, rarely, RRP-related mortality. Local immune tolerance within the airway mucosa is thought to impair clearance of HPV-6/11-infected cells, resulting in persistent infection and recurrent papilloma growth. Surgical debulking remains the cornerstone of management; however, JoRRP requires substantially more procedures than AoRRP (4-8 vs 1-2 per year), leading to cumulative morbidity, including vocal fold scarring, anterior commissure webbing, glottic or subglottic stenosis, and pulmonary dissemination. Defective innate immune activation and impaired HPV-specific cellular immunity contribute to viral persistence, with the papilloma microenvironment characterized by ineffective antiviral T-cell responses. To reduce surgical burden, immunotherapeutic strategies targeting HPV-6/11 antigens have been developed. Three platforms have advanced into phase 1-2 clinical trials: a gorilla adenoviral vector (gAdeno)-based therapy, a DNA plasmid vaccine, both encoding HPV-6/HPV-11 E6/E7 oncoproteins, and a Modified Vaccinia Ankara (MVA)-based bovine papillomavirus E2 vaccine. These approaches aim to elicit robust E6/E7-specific cellular immunity, particularly CD8+ T-cell responses, to overcome local immune tolerance and eradicate HPV-infected cells. The gAdeno-based therapy is the first FDA-approved immunotherapy for RRP; however, with annual treatment costs exceeding USD 300,000, ensuring equitable access remains a critical challenge.
2026-01-16 | Recurrent Respiratory Papillomatosis Foundation Position Statement on the Management of Adults With RRP.
With regulatory approval of HPV-specific immunotherapy for recurrent respiratory papillomatosis (RRP) and growing experience with systemic bevacizumab, a management algorithm incorporating these medical treatments is warranted. RRP Foundation (RRPF) Key Opinion Leaders offer a proposed management algorithm for adults with RRP considering published literature and commercial drug availability. Preventative HPV vaccination should be considered for all patients. Determination of HPV type and pulmonary imaging are important for contemporary RRP patient care and assist in decision making. Risks and benefits of papilloma debulking as needed versus medical management of RRP must be deliberated on a patient case-by-case basis. HPV-specific immunotherapy that induces an HPV-specific T cell response to target the underlying HPV infection that is the cause of RRP is safe, offers the possibility of durable disease control following a short treatment course and is the recommended first-line medical treatment for patients who wish to avoid the risks of repeat procedural management. Papilloma disease control with systemic bevacizumab, which carries defined risks and must be continued for clinical benefit is the recommended second-line medical treatment for patients who do not achieve a complete response with immunotherapy and wish to continue medical management. For patients who elect to be treated with debulking procedures as needed, use of locally-administered adjuvant should be considered. This proposed management algorithm from the RRPF serves as a contemporary resource and information guide for adult patients with RRP and their physicians considering treatment options.
2025-12-17 | Nationwide Survey on Recurrent Respiratory Papillomatosis in Japan: Analysis of Long-Term Patients.
To investigate the long-term disease status, clinical course, laryngeal distribution, management, and postoperative recurrence of recurrent respiratory papillomatosis (RRP) diagnosed before the first nationwide survey in Japan. As described in our previous report, we conducted a questionnaire-based survey targeting 782 institutions, asking about the presence of RRP patients during the survey period in 2018 and 2019. A detailed questionnaire was subsequently sent to the 196 institutions that reported having at least one patient, inquiring about age, sex, history of recent surgery, Derkay's score, surgical procedures, and postoperative recurrence. The present study analyzed data from patients who had been diagnosed prior to the beginning of the survey period. Data on 318 previously diagnosed patients were collected from 90 institutions. At their first follow-up visit during the survey period, 85 patients (26.7%) had a Derkay's anatomical score of 0. The true vocal folds were the most commonly affected laryngeal subsites. Of the 318 patients, 165 underwent surgery after the first follow-up visit, and recurrence occurred in 106 after this surgery. The 6- and 12-month additional surgery-free rates were 58.9% and 31.8%. These rates were significantly higher in patients who had undergone one or no surgery within a year prior to the first follow-up visit during the survey period than in those who had undergone two or more surgeries (p = 0.01). The present study revealed real-world data suggesting that the number of recent surgeries and Derkay's anatomical score may be associated with the clinical course of previously diagnosed RRP.
2025-11-01 | 1302 Zopapogene imadenovec, a novel HPV-targeted immuno-activator, induces complete and durable responses in recurrent respiratory papillomatosis patients
Background Recurrent respiratory papillomatosis (RRP) is a rare, neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Significant morbidity can occur due to airway obstruction and transformation into malignant cancer can occur. Zopapogene imadenovec (PAPZIMEOSTM) , a novel HPV-Targeted Immuno-Activator, is the first and only FDA-approved treatment for adults with RRP, and set to be the new standard of care treatment.Methods The pivotal trial ( NCT04724980) evaluated safety and efficacy in adult patients with RRP treated with 4 subcutaneous injections of zopapogene imadenovec (5x1011 particle units per injection; n=35). Zopapogene imadenovec was well-tolerated, with no serious adverse events, no grade >2 treatment-related adverse events, and no early treatment discontinuations. Most common adverse events were injection-site reaction, fatigue, chills, fever, and myalgia. Robust efficacy was observed following the treatment, with 51.4% (95% CI: 34.0 to 68.6) of patients achieving a Complete Response (CR), defined as no requirement for interventions in the 12m following treatment and 86% (30/35) of patients experienced a decrease in interventions.Results As of March 20, 2025, median duration of follow-up for all 35 patients was 30.3m (5 – 36). No new safety events were observed during long-term follow-up.Of 18 initial protocol-defined CRs, 15 (83%) remain in CR with median duration of follow-up of 34m (24-36). Median duration of CR has yet to be reached. 58% (95% CI: 39.1 to 75.5; n=31) and 83% (95% CI: 51.6 to 97.9; n=12) of evaluable patients did not require any interventions in year (Y) 2 and Y3 respectively. 90% and 91% of evaluable patients experienced a decrease in the number of interventions in Y2 and Y3 respectively compared to their 12m pre-treatment period.The development of HPV-specific T cell response post treatment assessed via IFN-γ ELISpot assay demonstrated that zopapogene imadenovec treatment stimulates the induction of HPV-specific T-cells and the magnitude of T-cell response was significantly higher in patients achieving CR or Partial Response compared to non-responders (mean fold-change 164.9 vs 5.1, P<0.018).Neutralizing antibody (NAb) titers collected up to 52-weeks post-treatment remained at little to low levels and there was no correlation between NAb incidence or titer and clinical response.Conclusions These data demonstrate that patients treated with zopapogene imadenovec either maintained consistent CRs for up to 3 years or demonstrated a reduction in the need for clinically indicated interventions following recurrence with excellent long-term safety.Ethics Approval The study obtained ethics approval from the NIH Intramural IRB, 6700B Rockledge Drive, Ste. 4300 Bethesda, Maryland USA 20817. The number/ID of the approval(s) are as follows: IRB ID: 21C0013/ MOD002946 IRB ID: 21C0013/ MOD004094 IRB ID: 21C0013/ MOD001703 IRB ID: 21C0013/ MOD002083 IRB ID: 21C0013/ MOD010746 IRB ID: 21C0013/ MOD006823 IRB ID: 21C0013/ MOD002680 IRB ID: All study participants gave informed consent before taking part and were reconsented according to the NIH IRB guidelines.
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2026-08-17 | Updated Practice Patterns for Adjuvant Treatment of Recurrent Laryngeal Papillomatosis.
Adjuvant medical treatments are used to reduce recurrence rates of recurrent respiratory papillomatosis (RRP). Prior consensus statements on initiation of adjuvants may not reflect current practices, particularly given safety data published in the interval. The objective of this study is to distribute information on current practices in management of RRP, including the use of adjuvant medications, use of surgical modalities and other treatments, monitoring, as well as attitudes and philosophies. Survey study. Email-distributed survey. A survey was distributed to a large group of laryngologists and pediatric otolaryngologists and responses were collected and analyzed. Responses were collected from 86 surgeons, including 71 specific to adult patients and 16 specific to pediatric patients. Laryngologists reported a threshold of 2 surgeries per year to initiate intralesional adjuvant treatments, while pediatric otolaryngologists reported thresholds of 4 surgeries per year for intralesional bevacizumab and 5 surgeries per year for cidofovir. Variable responses between groups were reported for other factors leading to initiation of adjuvants, surgical tools used, practices around HPV vaccination and testing, monitoring, and attitudes and philosophies regarding treatment of RRP. Current practice patterns and attitudes reflect increased comfort with the initiation of adjuvant treatments earlier in the disease course. New medical treatments that promise a shift away from primarily surgical treatment are highly anticipated.
2026-06-02 | Clonal expansion and phenotypic alterations of TCR Vβ3+ T cells in juvenile-onset recurrent respiratory papillomatosis: implications for tumor-associated immunity and chemokine-mediated T-cell trafficking.
Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare, human papillomavirus (HPV)-driven pediatric disease characterized by recurring papillomas in the respiratory tract. The contribution of dysregulated T-cell immunity to disease severity remains poorly understood. This study included 97 JORRP patients and 124 controls. Due to sample limitations, downstream analyses, including flow cytometry, TCR, and RNA sequencing, were performed on distinct patient subsets (detailed in Methods). We identified a selective expansion of TCR Vβ3+ T cells, including expanded TRBV28 clonotypes, in patients with aggressive disease. These T cells exhibited heightened cytotoxicity and activation markers, and were enriched in papilloma tissues. Within the tumor microenvironment, gene expression profiling revealed upregulated chemokine signaling pathways (CCR2/CCL7, CXCR6/CXCL16) and key immunosuppressive markers, including PD-L1 and TGF-β1. Our findings demonstrate a tumor-specific clonal expansion and functional alteration of TCR Vβ3+ T cells in JORRP, suggesting these pathways as preliminary targets for further investigation.IMPORTANCEOur study identifies a disease-specific T-cell signature in juvenile-onset recurrent respiratory papillomatosis (JORRP), marked by the clonal expansion of TCR Vβ3+ T cells with distinct TRBV28-dominant clonotypes. These T cells exhibit heightened cytotoxic potential and activation markers but appear functionally constrained within an immunosuppressive tumor microenvironment. Additionally, we discovered a dysregulated chemokine axis (CCR2/CCL7 and CXCR6/CXCL16), which likely facilitates T-cell recruitment, yet fails to sustain their antiviral activity. These findings provide mechanistic insights into why HPV-driven papillomas persist despite immune infiltration. Importantly, our work suggests that targeting TCR Vβ3+ T-cell responses and modulating key chemokine pathways could offer novel immunotherapeutic strategies to restore immune control and reduce disease recurrence in JORRP patients.
2026-05-01 | C67-20 A Case of Recurrent Respiratory Papillomatosis Treated With Bevacizumab and Nivolumab
Abstract A 24-year-old man was diagnosed at age 4 with recurrent respiratory papillomatosis (RRP), +HPV, low-risk category. He has had repeated laryngeal and tracheal debridement of airway papillomas. He has also had recurrent hemoptysis. Chest imaging has shown multiple solid and cavitating nodules, bronchiectasis, and thin-walled cysts. He was initially treated with 20 cycles of bevacizumab, with a marked improvement in his laryngeal disease. However, his pulmonary disease continued to progress. In May 2020, bevacizumab was discontinued, and he was started on nivolumab based on a published case series in refractory RRP. Although there was radiologic evidence of improvement in his pulmonary disease, his laryngeal papillomatosis worsened over 4 months of nivolumab therapy. In September 2020, in an effort to control both his pulmonary and upper airway disease, the patient was started on combination therapy with nivolumab and bevacizumab every 3 weeks. His disease remained stable for almost 2 years, until he was hospitalized for an intracranial abscess. His RRP treatment was held for several months. In February 2023, he was admitted for hemoptysis and ultimately underwent lobectomy for a cavitating lesion in the RLL. He remained off any therapy for over a year with close surveillance. During this period, he had increased growth of his laryngeal papillomas and was restarted on bevacizumab. Once again, his upper airway disease responded well, but he had progression of his pulmonary disease. He is currently on bevacizumab and nivolumab every 2 weeks. His laryngeal disease remains under control, with a mixed response in his chest. RRP is a disease caused by chronic infection of HPV-6 and HPV-11 with predilection for the respiratory epithelium. In the 8.9% of RRP patients with pulmonary involvement, there is a significant increase in morbidity as well as lifetime risk of malignant transformation. Small trials have shown positive results with bevacizumab therapy in patients with RRP, including those with pulmonary involvement. However, there are no available systemic treatments for refractory disease. A previous case series of 2 patients with refractory RRP demonstrated some clinical benefit of nivolumab. The decision to trial combination therapy with a VEGF inhibitor and PD-1 blocker in this patient was based on a Phase II trial suggesting clinical efficacy in relapsed ovarian cancer. To our knowledge, this is the first report of combined bevacizumab and nivolumab for RRP. While this patient’s pulmonary disease showed some response to therapy, clearly, more clinical trials are needed. This abstract is funded by: None
2025-10-07 | Prolonged Treatment Gaps and Recurrence Patterns in Recurrent Respiratory Papillomatosis.
Recurrent respiratory papillomatosis (RRP) is characterized by an irregular disease course, with recurrences after long periods of remission. New immunologic strategies are under investigation that aim to eliminate the chronic HPV infection. We evaluated recurrence patterns in RRP patients and sought to identify variables associated with prolonged remission periods. Charts of all RRP patients seen since 2003 at our institution were reviewed. Surgical history and disease status in treatment-free intervals were evaluated. Patient and disease characteristics were compared using chi-squared and Fisher's exact tests in an exploratory analysis. Of 312 RRP patients, 71 (22.8%) experienced a treatment gap (TG) of at least 4 years between treatment and recurrence, with 43 (13.8%) having a TG over 10 years. TG patients did not differ from the remaining cohort in sex, juvenile/adult onset, or other clinical characteristics. To control for the possibility that TG patients resembled the entire cohort because of untreated occult disease, a subset was identified with prolonged (≥ 4 years) definitive remission. Compared to this remission group, TG patients were more likely to undergo surgery rather than office procedures before the gap in treatment (100% vs. 71.4% p = 0.003) and less likely to have supraglottic disease (17.5% vs. 57.1% p = 0.012). Other patient characteristics showed no significant differences. A substantial portion of RRP patients experience recurrence after prolonged treatment-free intervals, and this cohort cannot be easily predicted from available clinical characteristics. This highlights the need for effective immunologic strategies to eliminate the causative chronic infection.
2025-07-11 | Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis.
Human papillomavirus-mediated recurrent respiratory papillomatosis (RRP) is a premalignant neoplasia of the upper airway characterized by significant dysphonia and respiratory obstruction. Immune checkpoint blockade has emerged as a potential alternative to repeated surgical interventions in RRP. Here, we investigated the intralesional T-cell composition and expression of the immune checkpoints programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) in RRP. We analyzed tissue samples from 30 patients treated at a tertiary care center between 2009 and 2021, including paired samples from individual patients collected at different time points. Immunohistochemical staining was performed for CD4, CD8, CTLA-4, FoxP3, and PD-L1 and correlated with disease severity and previous adjuvant therapies. Overall disease burden and intervention-free survival were not associated with the abundance of CD4+, CD8+, or FoxP3+ T cells, nor with immune checkpoint expression. However, patients with aggressive disease exhibited a higher intralesional FoxP3/CD4 T-cell ratio. Prior intralesional cidofovir treatment was associated with reduced CD4+ T-cell infiltration. These findings suggest that a locally immunosuppressive microenvironment, reflected by an elevated FoxP3/CD4 ratio, contributes to disease severity in RRP. Consistent CTLA-4 expression across all evaluated samples supports further investigation of anti-CTLA-4 therapy, either alone or in combination with other checkpoint inhibitors.
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2026-07-28 | Combined Analysis of scRNA-seq and Bulk RNA-seq Sequencing Revealing the Heterogeneity of Recurrent Respiratory Papillomatosis and Key Molecular Mechanisms of Its Occurrence and Development.
Recurrent respiratory papillomatosis (RRP) is a benign tumor that is highly prone to recurrence and has the potential to become malignant, caused by human papillomavirus (HPV) infection. The underlying mechanism is unclear, and new targets need to be explored urgently. This study integrated single-cell and bulk RNA-seq data, screened key genes through cell communication, machine learning, and animal models, constructed a predictive model, and completed drug prediction and independent validation. This single-cell sequencing study revealed an active fibroblast-epithelial dialogue within the RRP, and defined three subtypes of fibroblasts and their developmental trajectories. It identified key genes such as GJB2 and the ceRNA regulatory network, revealed imbalances in the immune microenvironment, and predicted potential therapeutic drugs. The key genes identified in this study, GJB2, IL36G, and S100A7, can serve as potential molecular markers and therapeutic targets for the early diagnosis, prognosis assessment, and precise treatment of RRP.
2026-07-09 | Zopapogene imadenovec-drba, a novel adenovector-based immunotherapy, induces complete and durable responses in recurrent respiratory papillomatosis
Robustefficacy was observedfollowing zopa treatment with 51% (34 to 69; 95% CI) of patients achieving a complete response (CR), defined as no requirement for interventions in the 12m following treatment.Here we present data up to 51m of followup. ResultsAs of December 15, 2025, with a median duration of follow-up of 36m (range: 30-51m), 83% (15/18) of patients who achieved a CR at 12m remainin CR with no recurrence of papilloma requiring surgicalor medical intervention.Out of the 15 patientsremaining in CR, 3 patients have reached 4 years of follow-up.No new safety events were observed during long-term follow-up. ConclusionsZopa treatment demonstrated significant clinicalbenefit with the vast majorityof CR patients experiencing ongoing durable complete responses for up to 4 years with excellent long-term safety.Updatedfollow-up results for all patientsachieving CR will be available at the time of presentation.
2026-05-27 | Zopapogene imadenovec-drba, a novel non-replicating adenoviral vector-based immunotherapy: Effects on complete and durable responses in recurrent respiratory papillomatosis pivotal trial.
6104 Background: Recurrent respiratory papillomatosis (RRP) is a rare, neoplastic disorder caused by chronic human papillomavirus (HPV) type 6 or 11 infection. Significant morbidity can occur due to airway obstruction and transformation into malignant cancer. Repeat surgical debulking has historically been the most common treatment for RRP symptom management. Zopapogene imadenovec-drba (zopa), a novel adenoviral vector-based immunotherapy, is the first and only FDA-approved treatment for adults with RRP. Zopa is now recommended as the first-line treatment for adults with RRP in an RRP Foundation position statement authored by 16 key opinion leaders (Best et al. Laryngoscope 2026). Methods: The pivotal trial (NCT04724980) evaluated zopa in patients with RRP requiring ≥3 clinically indicated interventions 12 months (m) prior to treatment. 12m follow-up data was reported and demonstrated that 4 subcutaneous injections of zopa (5x10 11 particle units per injection; n=35) were well-tolerated, with no serious adverse events, no grade >2 treatment-related adverse events, and no early treatment discontinuations. The most common adverse events were injection-site reaction, fatigue, chills, fever, and myalgia. Robust efficacy was observed following zopa treatment with 51% (34 to 69; 95% CI) of patients achieving a complete response (CR), defined as no requirement for interventions in the 12m following treatment, and 86% (30/35) of patients experiencing a decrease in interventions in the year following treatment as compared to the year prior to treatment. Here we present data up to 51m of follow-up. Results: As of December 15, 2025, 83% (15/18) of patients who achieved a CR at 12m remain in CR with no recurrence of papilloma requiring surgical or medical intervention. The median duration of follow-up for patients in CR was 36m (range: 30-51m), with 3 patients having a response lasting more than 4 years. No new safety events were observed during long-term follow-up. Conclusions: Zopa treatment demonstrated significant clinical benefit with the vast majority of CR patients experiencing ongoing durable complete responses for up to 4 years with excellent long-term safety. Updated follow-up results for all patients achieving CR will be available at the time of presentation. Clinical trial information: NCT04724980 .
2026-05-09 | The Efficacy and Safety of Systemic Treatment for Managing Recurrent Respiratory Papillomatosis: A Systematic Review and Meta-analysis.
Surgical treatment remains the cornerstone of recurrent respiratory papillomatosis (RRP) management; however, aggressive disease often requires frequent procedures with cumulative morbidity. Contemporary systemic options now include systemic bevacizumab and human papillomavirus (HPV)-specific immunotherapies, with immune checkpoint inhibition under investigation. We systematically reviewed the efficacy and safety of systemic therapies for juvenile- and adult-onset RRP, emphasizing current clinician-relevant treatment options. We comprehensively searched PubMed, Scopus, Web of Science, and the Cochrane Library from inception until January 2026. The included studies evaluated any available systemic treatment for managing adult or juvenile-onset RRP. The main outcomes were complete remission, partial response, and adverse events. All the data analyses were performed using STATA 18 BE. We included 35 studies comprising 925 patients. In juvenile-onset RRP, pooled complete remission with systemic bevacizumab was 60% (95% CI 34-87%), and pooled partial response was 46% (95% CI 21-71%). In adult-onset RRP, pooled complete remission with systemic bevacizumab was 44% (95% CI 26-62%), and pooled partial response was 61% (95% CI 43-79%). The most frequently reported bevacizumab adverse events were hypertension (40%), proteinuria (26%), and epistaxis (22%). HPV-specific immunotherapies (including FDA-approved zopapogene imadenovec-drba [Papzimeos; PRGN-2012] for adults and investigational INO-3107) and PD-1/PD-L1-directed therapies demonstrated encouraging early-phase activity but were too heterogeneous for quantitative pooling. Systemic bevacizumab remains the most mature systemic option with consistent real-world evidence and published dosing guidance. HPV-specific immunotherapy has recently transformed adult RRP management with an FDA-approved, short-course treatment option; ongoing studies will clarify optimal sequencing with bevacizumab and the role of checkpoint inhibition.
2025-12-01 | Modeling and Exploring Recurrent Respiratory Papillomatosis with 3D Cell Cultures
Recurrent respiratory papillomatosis (RRP) is a benign but potentially life-threatening tumor of the airway epithelium that is caused by persistent infection with low-risk human papillomavirus (LR-HPV) type 6 or 11. Current management relies on repeated surgical removal of lesions, as no curative antiviral therapy is available, imposing substantial physical and psychological burden on patients. To develop novel therapeutic strategies, it is essential to elucidate the mechanisms by which LR-HPVs persist, replicate, and drive tumor formation. However, the lack of in vitro models that recapitulate the viral life cycle has hindered its progress. In this study, we established primary epithelial cell cultures from surgical RRP specimens using conditional reprogramming (CR) with J2 feeder fibroblasts and a ROCK inhibitor, achieving a high success rate (～90%). These cells retained LR-HPV genomes and were adaptable to three-dimensional (3D) culture, forming spheroid structures that mimicked in vivo tissue architecture and preserved proliferative and undifferentiated phenotypes. Immunostaining and molecular analyses revealed suppressed cGAS-STING pathway activity and reduced type I interferon response in RRP-derived cells, suggesting impaired innate immune surveillance. This 3D CR-based model provides a robust platform for investigating the pathogenesis of LR-HPV and host–virus interactions, potentially accelerating the development of targeted therapies for RRP.
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Drug Discovery Landscape
11 orphan drug designations for Recurrent respiratory papillomatosis, including 1 approved therapy.
11 orphan drug designations for Recurrent respiratory papillomatosis, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
a single recombinant plasmid-derived DNA-based therapeutic vaccine specifically targeting the E6 and E7 antigens of both HPV 6 and HPV 11 | vaccines | FDA | — | Advaccine Biopharmaceuticals Suzhou Co., Ltd. |
pembrolizumab | antibodies | FDA | Massachusetts General Hospital | |
bevacizumab | antibodies | FDA | DELBERT SAS | |
Gorilla adenovirus vector expressing HPV6 and HPV11 antigens | gene therapies | EMA | — | FGK Representative Service GmbH |
Doruxapapogene ralaplasmid | gene therapies | EMA | — | PHARA |
zopapogene imadenovec-drba [Papzimeos] | gene therapies | FDA | Approved | Precigen, Inc. |
A recombinant plasmid-derived DNA-based vaccine targeting the E6 and E7 antigens of both HPV6 and HPV11 | oligonucleotides | FDA | Inovio Pharmaceuticals, Inc. | |
modified vitamin D binding protein | proteins | FDA | Efranat, Ltd. | |
Recombinant fusion protein of Mycobacterium bovis BCG Hsp65 and HPV16 E7 | proteins | FDA | — | StressGen Biotechnologies, Inc. is now Nventa |
Interferon alfa-2b (recombinant) | proteins | FDA | — | Schering Corporation |
Interferon alfa-nl | proteins | FDA | — | Glaxo Wellcome Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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