Novel IO Vaccine Induces Immune Response HPV16-Positive Tumors

A first-in-human study investigating the safety and immunogenicity of amplivant adjuvant and human papillomavirus type 16 synthetic long peptides demonstrated highly favorable safety and tolerability when used as an intradermal therapeutic vaccine.

Amplivant-conjugated synthetic long peptides (SLPs) can be safely used as an intradermal therapeutic vaccine to induce human papillomavirus type 16 (HPV16)-specific T cell immunity in patients who were previously treated with HPV16-positive pre-malignancies, according to findings from a phase 1 study announced by ISA Pharmaceuticals B.V.1

Amplivant is a molecularly optimized toll-like receptor 1/2 ligand. The agent can be covalently conjugated to tumor peptide antigens. Preclinical models evaluating amplivant-adjuvanted SLPs have shown them to strongly enhance antigen presentation by dendritic cells, T-cell priming, and induce effective antitumor responses.

In the first-in-human, dose-escalation, phase 1 study, investigators aimed to establish the highest dose that was safe to induce HPV16 E6-specific T-cell responses. Amplivant was conjugated to 2 SLPs which were derived from the 2 most immunodominant regions of the HPV16 E6 oncoprotein.2

A total of 25 patients aged 18 years and older with histologically documented evidence of HPV16 positive (pre)malignant lesion following standard treatment who have a tumor with no evidence of residual disease were enrolled in the trial. By the time of enrollment, it must have been at least 4 weeks and less than 12 weeks after last anti-tumor treatment, patients must have been in ​​ good general health and ambulatory and an ECOG performance status of 0-1.

Patients were given 3 doses intradermally, 3 times a week, and with a 3-week interval in 4 dose groups which included 1, 5, 20, or 50 µg per conjugated peptide. Peptide-specific T cell immune responses were determined in peripheral blood mononuclear cells from blood samples taken before, during, and after vaccination.

In 25 patients, vaccine dose escalation led to a corresponding increase in systemic T cell immunity.

The primary end point of the trial was the biological activity of the dose escalation of Amplivant conjugated peptide, and the secondary end point was safety, including evaluating adverse events (AEs).

The combination elicited a significant, strong immune response, and dose related systemic T-cell immunity when injected intradermally. Further, a favorable safety profile was seen with no serious AEs.3

After 3 amplivant-conjugated HPV16-SLP vaccinations, the observed toxicities were limited to grade 1 or 2 and included mild skin inflammation at the vaccination site and mild flu-like symptoms. No AEs were observed in the lowest dose group. In the highest dose group, patients had mild or moderate vaccine-related inflammation and 3 of the 7 patients enrolled into this cohort had flu-like symptoms after at least 1 injection.

Vaccine-induced T-cell responses were also observed in the blood of 3 out of 6 vaccinated patients in the lowest dose group while in the highest dose group, all patients had a strong HPV16-specific T cell response after vaccination. HPV16-specific T cell responses contained in patients until the end of the trial.

These findings show amplivant-conjugated SLPs are safe when used as an intradermal therapeutic vaccine to induce HPV16-specific T cell immunity in patients with previously treated HPV16-positive (pre-)malignancies as there were minimal AEs observed.

REFERENCE:
  1. First-in-human study: Amplivant® adjuvant boosts immune response of synthetic long peptide immunotherapy. News release. ISA Pharmaceuticals. November 8, 2022. Accessed November 9, 2022. https://prn.to/3FWXMgn
  2. Hespecta vaccination in HPV+ tumors or malignant lesions. ClinicalTrials.gov. Updated February 21, 2021. Accessed November 8, 2022. https://clinicaltrials.gov/ct2/show/NCT02821494?term=NCT02821494&draw=2&rank=1
  3. 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 HPV-16 positive (pre-)malignant lesions. J Immunother Cancer. 2022;10(10):e005016. doi:10.1136/jitc-2022-005016