title: 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 p16(INK4a) is strongly and consistently overexpressed in all human papillomavirus (HPV)-associated cancers. Therefore, the authors hypothesized that p16(INK4a) 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 p16(INK4a) -based peptide vaccine.
  
  
  METHODS
  A total of 26 patients with different, advanced, p16(INK4a) -overexpressing, HPV DNA-positive cancers were included after the completion of standard treatment. According to protocol, 12 subcutaneous injections of a p16(INK4) 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 p16(INK4a) -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 p16(INK4a) -based cancer immunotherapeutics. Cancer 2016;122:1425-1433. © 2016 American Cancer Society.
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Reuschenbach
authors.affiliation: Institute for Clinical Research, Northwest Hospital, Frankfurt, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pauligk
authors.affiliation: Department of Hematology-Oncology, Northwest Hospital, Frankfurt, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Karbach
authors.affiliation: Department of Hematology-Oncology, Northwest Hospital, Frankfurt, Germany.
authors.forename: Mohammad-Reza
authors.initials: MR
authors.lastname: Rafiyan
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Elena-Sophie
authors.initials: ES
authors.lastname: Prigge
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Sauer
authors.affiliation: Institute for Clinical Research, Northwest Hospital, Frankfurt, Germany.
authors.forename: Salah-Eddin
authors.initials: SE
authors.lastname: Al-Batran
authors.affiliation: Clinic for Gynecology, Berlin Charité University Medical Center, Berlin, Germany.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Kaufmann
authors.affiliation: Clinic for Gynecology, Berlin Charité University Medical Center, Berlin, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Department of Hematology-Oncology, Northwest Hospital, Frankfurt, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Jäger
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel Doeberitz
mesh_terms: D000328:Adult; D000368:Aged; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D000071497:Immunogenicity, Vaccine; D008297:Male; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000628:therapy*; D022223:Vaccines, Subunit / Q000009:adverse effects / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D019941:Cyclin-Dependent Kinase Inhibitor p16; D022223:Vaccines, Subunit; D014764:Viral Proteins
keywords: cervical cancer; head and neck cancer; human papillomavirus; p16INK4a; peptide vaccine