Beyond anti–PD-1 therapy as a mainstay, additional strategies are being developed for HPV-associated cancers. Emerging data from two ongoing trials have shown some early efficacy with vaccines directed at HPV16-specific E6 and E7 viral oncoproteins, as well as with other therapies targeting different facets of antitumor immunity.

Immunotherapies targeting the PD-1 axis have become a mainstay in treating cancers associated with human papillomavirus (HPV). Both nivolumab (Opdivo; Bristol Myers Squibb) and pembrolizumab (Keytruda; Merck) are approved for head and neck squamous cell carcinoma (HNSCC); the latter is also indicated for PD-L1+ cervical cancer. However, additional strategies are needed.

“The response rate of HPV-related malignancies to anti–PD-1 therapy is between 13% to 24%, but for the overwhelming majority of patients with eventual disease progression, there is no effective standard of care,” said Julius Strauss, MD, of the NCI. During the American Society of Clinical Oncology 2021 Annual Meeting, June 4–8, he reported results from an ongoing phase II trial evaluating a cocktail of three therapies, each stimulating a different facet of antitumor immunity.

Study participants received a triple combination of PDS0101 (PDS Biotech), M9241 (EMD Serono), and bintrafusp alfa (Merck KGaA/GlaxoSmithKline). PDS0101, a peptide-based vaccine, can induce strong CD4+ and CD8+ T-cell responses against E6 and E7, two viral oncoproteins specific to HPV16, the biggest culprit in HPV-associated cancers worldwide. M9241 is a tumor-targeting immunocytokine, Strauss explained. It delivers IL12 to the tumor microenvironment—thereby increasing T-cell infiltration—via a monoclonal antibody that detects and binds to free DNA fragments found in areas of tumor necrosis. As for bintrafusp alfa, this bifunctional fusion protein is designed to trap TGFβ and target PD-L1, keeping two immunosuppressive pathways in check.

Strauss and his colleagues chose this cocktail because “preclinically, we saw maximum HPV-specific T-cell responses, tumor infiltration, and tumor reduction when all three agents were given together, compared with any one or two alone,” he said. So far, 25 patients with HNSCC, cervical, anal, and vaginal cancers have been treated; 18 were genotyped as HPV16+.

Among the HPV16+ patients, the objective response rate (ORR) was 55.6%, including two complete responses. Six of 18 had not received prior checkpoint immunotherapy; their ORR was 83.3% and, at a median follow-up of 8 months, “all remain alive,” Strauss said. The other 12 patients had checkpoint inhibitor–refractory disease; their ORR was 41.7%, but “the majority had tumor shrinkage, and 10 of 12 are alive,” he added—which is favorable compared with the historical median overall survival of 3 to 4 months.

Discussant John Hyngstrom, MD, of Huntsman Cancer Institute in Salt Lake City, UT, noted that “despite the triple combination having potential for morbidity, the safety profile was reasonable.” Anemia, flu-like symptoms, and lymphopenia were the main, clinically manageable side effects.

Alan Ho, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, presented emerging data from a phase I/II study of two arenavirus-based vaccines, HB-201 and HB-202 (Hookipa Pharma). Both are “engineered to express a nononcogenic E6/E7 fusion protein, inducing robust antigen-specific T-cell responses in HPV16+ tumors,” he explained.

The trial is still in the dose-escalation phase, with investigators assessing different treatment schedules in two cohorts—one comprising patients with HPV16+ HNSCC; the second, other HPV16+ cancers. Both groups are receiving either intravenous HB-201 monotherapy or HB-201 alternating with HB-202.

Preliminary efficacy has been seen, notably in those treated every 3 weeks, Ho observed. Among 11 evaluable patients with HNSCC given the two lowest doses of HB-201 alone, two had partial responses; six more experienced stable disease. In the other cohort, all four evaluable patients given the lowest dose of HB-201/HB-202 had stable disease. Side effects, including fatigue and fever, were low grade.

“We're also seeing signs of immunogenicity, which is important proof-of-principle,” Ho said. “Up to 40% of circulating CD8+ T cells analyzed were E6/E7-specific and polyfunctional, producing IFNγ and TNFα.”

These data “speak to the [vaccines'] priming potential in future combinations with checkpoint blockade, for instance, to augment response,” Hyngstrom remarked. Both Strauss and Ho highlighted “novel exploitations of viral antigens,” he added, with “promising initial efficacy that, hopefully, can be capitalized with larger studies and longer follow-up.” –Alissa Poh