A phase 1/2a study to test the safety and immunogenicity of a p16^INK4a peptide vaccine in patients with advanced human papillomavirus‐associated cancers

Abstract

BACKGROUND The cyclin‐dependent kinase inhibitor p16INK4a is strongly and consistently overexpressed in all human papillomavirus (HPV)‐associated cancers. Therefore, the authors hypothesized that p16INK4a may be a vaccine target antigen for HPV‐associated cancers. To test this hypothesis, the authors performed a phase 1/2a first‐in‐human trial to evaluate the safety and immunogenicity of a p16INK4a‐based peptide vaccine. METHODS A total of 26 patients with different, advanced, p16INK4a‐overexpressing, HPV DNA‐positive cancers were included after the completion of standard treatment. According to protocol, 12 subcutaneous injections of a p16INK4 peptide (P16_37‐63) mixed in a water‐in‐oil emulsion with immunoadjuvant activity (Montanide ISA‐51 VG) were administered over a 6‐month period. RESULTS A total of 20 patients received at least 4 injections and were evaluable for immune responses against P16_37‐63. Clusters of differentiation (CD) 4 T cells were detected in 14 of 20 patients (3 of whom had preexisting CD4 T cells before vaccination), CD8 T cells were detected in 5 of 20 patients, and antibodies were detected in 14 of 20 patients (1 of whom had preexisting antibodies). No suspected unexpected serious adverse reaction or serious adverse drug reaction was documented. All reported serious adverse events were expected and not considered to be related to study therapy. None of the patients discontinued trial participation due to unacceptable toxicities and no dose‐limiting toxicities occurred. Tumor response could be assessed in 14 patients. Of these, 9 patients (64%) had stable disease as their best overall response and 5 patients (36%) developed progressive disease. CONCLUSIONS Vaccination with the p16INK4a‐derived peptide P16_37‐63 appears to induce cellular and humoral immune responses and does not cause severe toxicities. The results of the current study pave the way for the further clinical development of p16INK4a‐based cancer immunotherapeutics. Cancer 2016;122:1425–1433. © 2016 American Cancer Society.

The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution

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Enhanced and long term immunogenicity of a Her-2/neu multi-epitope vaccine conjugated to the carrier CRM197 in conjunction with the adjuvant Montanide

“…The study has shown that all subjects experienced one or more treatment-emergent adverse effects of general disorders, administration site conditions or gastrointestinal disorders, however less frequent adverse effects were observed in the subjects receiving the lowest dose (30 μg) and in overall the trial treatment was well tolerated with local injection-site reaction being the most frequent adverse effect [ 33 ]. In an additional phase 1/2a study, enrolling patients with advanced human papillomavirus-associated cancers and using the ISA-51VG adjuvant, mild injection site reactions were found to be related to the study treatment while all reported serious adverse events were unrelated to the study treatment [ 34 ].…”