Gene Therapy Stabilizes Rare Chronic HPV Disease

For recurrent respiratory papillomatosis (RRP), novel gene therapy to jump-start immunity to the human papillomavirus (HPV) that causes it was safe and yielded complete response in many cases, a small pivotal trial showed.

Fully 51% (18) of the 35 patients treated at the recommended phase II dose of PRGN-2012 had a complete response, defined by no clinically indicated interventions in the year following treatment.

Notably, these patients had required a median of four and up to 10 laser ablation or surgical procedures to treat the recurrent disease in the 12 months before the trial, reported researchers led by Scott Norberg, DO, of the NIH Center for Immuno-Oncology in Bethesda, Maryland.

The median duration of complete response was yet to be reached at 12-month follow-up, and 83% (13) of the 18 responders remained so beyond the 12 months to a median follow-up of 22 months.

While just a single-center, single-arm, phase I/II trial, it will be the basis for application to the FDA for accelerated approval as the first systemic treatment for RRP in adults, the researchers noted in their paper in Lancet Respiratory Medicine.

Spontaneous change in the tempo of surgeries due to improvement in the condition is unlikely, so the results are “highly likely” to be due to the gene therapy, noted an accompanying editorial by Craig Derkay, MD, of Eastern Virginia Medical School in Norfolk.

“This is a potentially game-changing treatment for adults with severe RRP, which is a very challenging disease to treat and exacts a tremendous toll on patients through the requirement for repeated surgeries,” he wrote. “Any new clinical intervention that reduces the need for surgery is a breakthrough because no current therapeutics are licensed for treatment of this disorder.”

Chronic infection with HPV subtypes 6 and 11 is responsible for the vast majority of RRP, which is considered rare at an incidence of two per 100,000 persons in the United States. The condition causes persistent papillomas predominantly in the larynx, trachea, and lungs. Standard treatment — repeated laser ablation and surgical excision of papillomas — to preserve the larynx and a patent airway can cause irreversible airway damage over the hundreds of procedures patients may require over their lifetime.

Previous attempts with nonspecific immunotherapies, such as systemic interferon or immune checkpoint blockade, haven’t panned out in RRP, Derkay noted.

The trial serves as “proof-of-concept that T cells that are HPV-specific are activated to directly attack the papillomas,” he wrote. PRGN-2012 uses a gorilla adenovirus vector to deliver gene therapy to elicit robust T-cell immunity specific to HPV 6 or 11. A second gene therapy candidate that spurs antigen-specific T cell response against both HPV-6 and HPV-11 proteins showed a nearly 50% complete response rate at 1 year in a phase II study done by Inovio.

“A novel approach using immunotherapy might eventually allow for cure of RRP and other HPV-mediated disease,” Derkay suggested.

In the trial, patients got standard surgery for the disease at baseline and then four subcutaneous administrations of adjuvant PRGN-2012 over the course of 12 weeks, with up to two optional debulking surgeries to maintain minimal residual disease if papilloma regrew during this period. Both the initial surgery and any needed to maintain minimal residual disease were performed at the NIH Clinical Center by a single surgeon.

Need for pretrial interventions and those more than 12 months after treatment were determined by the patient’s usual-care otolaryngologist without involvement of the study team.

The 35 patients (57% male) treated at the recommended phase II dose (out of a total 38 treated across the phase I and II trials) had been diagnosed at a median 35 years of age and started treatment at a median of 49 years.

Most of the participants (66%) had adult-onset disease, but the response rate was similar between them and those with juvenile-onset RRP.

No serious adverse events, grade 3 or worse treatment-related adverse events, or early treatment discontinuations occurred. Most adverse events were mild; most common among them were grade 1-2 injection site reactions (97%), fatigue (80%), chills (71%), and fever (69%).

One death from cardiogenic shock following myocardial infarction was deemed due to a previous history of coronary artery disease and severe aortic stenosis rather than the study drug.

One limitation of the trial was lack of biopsy of visibly normal laryngeal mucosa to determine whether HPV infection was completely cleared in patients with complete responses. “Therefore, it is unknown whether these patients have been cured,” the researchers noted. “Longer follow-up will help determine whether the clinical course of RRP has been permanently affected by PRGN-2012 treatment.”

Phase III trials are being planned to confirm durability of the results with both PRGN-2012 and the Inovio agent and to determine if a booster dose might help or what factors differentiate those who don’t respond, Derkay noted.

“Future studies looking at whether combination therapies with additional systemic agents (immune-checkpoint inhibitors or bevacizumab [Avastin] biosimilars) might alter the papilloma microenvironment to become more supportive of HPV-specific T-cell immunity, potentially resulting in a greater proportion of patients with RRP reaching durable disease control, will be the focus of ongoing research,” he added.