xRead - Recurrent Respiratory Papillomatosis (October 2025)

Article

https://doi.org/10.1038/s41467-025-56729-6

(10, 31.3%) were infected with HPV-11 only, and two (2, 6.3%) were co infected with both HPV-6 and HPV-11. Four (4, 12.5%) patients ’ geno types could not be distinguished between HPV-6 and HPV-11 per assay standards at Screening but were known from prior diagnostic history to be HPV-6 and/or HPV-11 positive, which was subsequently con fi rmed through on-study assessment. All patients in the trial had complete follow-ups for ef fi cacy and safety data. Of the 32 patients, 26 had a clinical response (81.3%), de fi ned as a reduction of at least one surgical procedure in the year following Day 0 (overall clinical response; OCR). Nine patients (28.1%) had a complete response (CR), de fi ned as no surgical interventions in the year fol lowing Day 0, and 14 additional patients (43.8%) had a partial response (PR),de fi ned as a reduction in the number of surgical interventions by 50 – 99% in the year following Day 0 (Fig. 1). Together this represents an overall response rate (ORR) of 71.9%; 23 of 32 patients. Reduction in surgical frequency was independent of HPV genotype as responses were noted for patients exhibiting HPV-6 and/or HPV-11 per genotypic assessment (ORR of 66.7% for HPV-6, ORR of 83.4% for HPV-11). When comparing the median number of surgeries in the year prior to treatment with the year following Day 0, in the year prior, patients had a median of four surgeries (range 2 – 8), while in the year following treatment, there was a median decrease of three surgeries with a 95% con fi dence interval of 2 to 3, which indicates a statistically signi fi cant decrease. INO-3107 improves RRP severity scores in adults with RRP Treatment with INO-3107 resulted in reductions in RRP Severity Score (modi fi ed) from pretreatment through the treatment assessment period, as assessed by laryngoscopy throughout the trial. Anatomical disease severity was measured by a modi fi ed Derkay Score. Scores were obtained prior to surgery at or near Day 0, and again at each visit when laryngoscopy was performed. Between Day 365 and Day 0, there was a mean change in total site score of − 10.7 (95% CI − 16.3, − 5.0)anda mean change in total symptom score of − 0.4 (95%CI − 0.7, 0.0). The mean change in total clinical score (total site and total symptom score) was − 11.0 (95% CI − 16.7, − 5.3). INO-3107 is well tolerated in adults with RRP Treatment with INO-3107 was well tolerated in this trial. Twenty patients (62.5%) reported treatment-emergent adverse events (TEAEs), most of which were treatment-related (35/58 events), and almost all of which were Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2 in severity (54/58 events (Table 2)). All related TEAEs were Grade 1 or 2 in severity, and the most common related TEAE was injection site pain (10 patients); all other related TEAEs were seen in three patients or fewer (Table 2). Grade 3 TEAEs were observed in four (4) patients (12.5%), all of which were unrelated. Serious adverse events (SAE) were observed in three (3) patients (9.4%), none of which were considered treatment related. No patient experienced a Grade 4 or 5 TEAE or TEAE leading to treatment discontinuation or death. INO-3107 reduces or eliminates surgical intervention in the treatment of RRP INO-3107 induces HPV-6 and HPV-11-speci fi c T-cell responses and drives peripheral T-cell clonal expansion T-cell responses induced by INO-3107 were fi rst gauged via ex vivo interferon gamma (IFN γ ) ELISpot. T-cell reactivity against INO-3107 antigens was noted in 94% of patients (30/32) over the course of the trial and reactivity was con fi rmed individually for HPV-6 as well as HPV 11 (Fig. 2A and Supplementary Fig. 2). Upon con fi rmation of antigen-speci fi c T-cell responses in blood, multiparametric fl ow cytometry was employed to further elucidate

generating immunity against HPV itself. Patients suffering from RRP have been characterized as exhibiting suppressive or regulatory immune-related functions within papillomas, as opposed to mounting a cytotoxic response against HPV infected cells 9 – 13 . Our previous stu dies of DNA immunotherapies directed against HPV have demon strated the induction of potent immune responses for HPV in a pilot trial of adults with HPV-6-related RRP and in HPV-related head and neck squamous cell carcinoma as well as cervical disease, inclusive of the generation of HPV-speci fi c cytotoxic T-cells as well as CD8+ immune cell in fi ltration into tumors 14 – 18 . Additionally, other groups have conducted clinical studies of RRP treatment from an immuno logical approach via antibody and T-cell-related platforms, with results that support an immune-based impact on disease state 19,20 . INO-3107 is a DNA immunotherapy encoding for antigens from both HPV-6 and HPV-11 as well as encoding for an interleukin-12 (IL-12) immune adju vant. Here, we report full study results from a DNA-based therapy in development for RRP from a completed Phase 1/2 trial demonstrating the safety, ef fi cacy, and immune responses of INO-3107. Results Patient demographics A total of 32 patients were enrolled between October 2020 and November 2021, with follow-up completed through December 2022; seven (7) patients had juvenile-onset (JO) RRP and 25 had adult-onset (AO) RRP (Table 1). All patients completed all clinical trial visits up to Week 52. Demographics of the trial population are presented in Table 1. Sixteen (16, 50.0%) patients were infected with HPV-6 only, ten

Table 1 | Demographics and baseline characteristics (mITT population)

Parameter

Patients ( N =32)

Median age (range), years

47.3 (25-82)

Male, n (%) Race, n (%) Asian

24 (75.0)

1 (3.1)

Black or African American

4 (12.5)

White Other

26 (81.3)

1 (3.1)

Ethnicity, n (%)

Hispanic or Latino

3 (9.4)

Not Hispanic or Latino

29 (90.6)

Type, n (%) Juvenile Onset RRP (age at diagnosis <12years) Adult Onset RRP (age at diagnosis ≥ 12years) Number of surgeries in prior year, n (%) 2

7 (21.9)

25 (78.1)

6 (18.8)

3 to5

18 (56.3)

≥ 6

8 (25.0)

HPV genotype, n (%) 6

16 (50.0)

11

10 (31.3)

6and 11

2 (6.3)

6and/or 11 a

4 (12.5)

Median (range) number of surgeries in the year prior to dosing

4 (2 – 8)

mITT modi fi ed intention-to-treat, N or n number of patients; % percentile, RRP recurrent respiratory papillomatosis, HPV human papillomavirus. a Of the 32 patients, three (3) did not have papilloma tissue collected at Baseline and one (1) had the HPV genotyping assay fail. HPV-6 and/or 11 was con fi rmed prior to the study based on documentation provided by the clinical site for these four (4) patients, but the genotype was not speci fi ed.

Nature Communications | (2025)16:1518

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