Phase 1 Study Shows Signals of Response With Vaccine for HPV16+ Premalignancies

A vaccine comprised of amplivant-conjugated synthetic long peptides was found to be a feasible intradermal vaccine for inducing robust activity in patients with human papillomavirus (HPV) 16–positive premalignancies, according to the results of a phase 1 doseescalation trial (NCT02821494).

“This phase 1 vaccination study shows that intradermal administration of amplivant-conjugated [synthetic long peptides] is safe with only minimal and mostly local [adverse] effects,” the study authors, led by Frank M. Speetjens, MD, Department of Medical Oncology, Leiden University Medical Center, the Netherlands, wrote in their report published in the Journal for Immuno Therapy of Cancer.¹

Amplivant is a synthetic Toll-like receptor 2 ligand conjugated to a synthetic long peptide (SLP) to create a self-adjuvanting peptide vaccine. Such vaccines can activate the innate immune system, target antigens to dendritic cells, and activate dendritic cells, resulting in T-cell activation.

Investigators conducted a fi rst-in-human phase 1 trial of a vaccine of amplivant conjugated to HPV16 E6-SLP. Two SLPs were chosen based on patients who previously responded to vaccination.2 The 2 E6 peptides were selected as being the most immunodominant with both T-helper and cytotoxic T-lymphocyte epitopes.

The phase 1 study looked at safety and T-cell immunogenicity.¹ The vaccine was administered by intradermal injection given 3 times in a 3-week interval in 4 dose cohorts: 1 µg/conjugated peptide, 5 µg/conjugated peptide, 20 µg/conjugated peptide, and 50 µg/conjugated peptide.

Originally, the study investigators intended to enroll only patients with oropharyngeal squamous cell carcinoma after prior therapy, but due to slow accrual, the expanded the protocol to include patients with HPV16-positive pre-malignant lesions.

A total of 25 patients were enrolled between July 2015 and March 2020. Patients had to meet the inclusion criteria of having an HPV16-positive premalignant lesion following curative therapy, no residual disease after treatment, a World Health Organization performance score of 0 to 1, and adequate organ and bone marrow function.

The most common diagnosis across the 4 dose groups was oropharyngeal squamous cell carcinoma followed by high-grade squamous intraepithelial lesion. Most patients had T2 and N1 or N2 disease.

Patients in the higher-dose groups were more likely to respond to vaccination (P = .077). In the 50-.g group, more patients showed positive response after the third vaccination.

Using the 4-day IFN-γ ELISpot assay, investigators measured T-cell responses to the 2 vaccine peptides. Only 4 of 25 patients showed any response at baseline. After the second vaccination there was a significant increase in T-cell responses to both peptides compared with baseline measurements, which was not enhanced after the third vaccination. Two of 6 patients in the 1-.g group responded as well as 5 of 6 patients in the 5-µg group. In the higher-dose cohorts, all patients tested positive to 1 or both peptides. Overall, an increase in response was seen in the higher-dose levels (P = .004).

CD4-positive and CD8-positive T-cell responses were observed in selected patients to 1 or both vaccine peptides. However, CD4-positive responses were seen more often than CD8-positive responses.

All toxicities were grade 1 or 2 and no skin toxicity was observed. Vaccine-related inflammation was seen more commonly in the higher-dose cohorts. However, these reactions were generally resolved within 48 hours.

“Overall, the peptide conjugated vaccine showed potent immunogenicity and was able to induce functional T-cell responses in almost all vaccinated patients when applied in a 20-µg or higher dose,” Speetjens et al wrote.

_REFERENCES:

_{1. Speetjens FM, Welters MJP, Slingerland M, et al. Intradermal vaccination of HPV-16 E6 synthetic peptides conjugated to an optimized Toll-like receptor 2 ligand shows safety and potent T cell immunogenicity in patients with HPV16 positive (pre-)malignant lesions. J Immunother Cancer. 2022;10(10):e005016. doi:10.1136/jitc-2022-005016}

_{2. Melief CJM, Welters MJP, Vergote I, et al. Strong vaccine responses during chemotherapy are associated with prolonged cancer survival. Sci Transl Med. 2020;12(535):eaaz8235. doi:10.1126/scitranslmed.aaz8235}