title: Induction of robust type-I CD8+ T-cell responses in WHO grade 2 low-grade glioma patients receiving peptide-based vaccines in combination with poly-ICLC.
abstract: OBJECTIVE
  WHO grade 2 low-grade gliomas (LGG) with high risk factors for recurrence are mostly lethal despite current treatments. We conducted a phase I study to evaluate the safety and immunogenicity of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes in HLA-A2(+) adults with high-risk LGGs in the following three cohorts: (i) patients without prior progression, chemotherapy, or radiotherapy (RT); (ii) patients without prior progression or chemotherapy but with prior RT; and (iii) recurrent patients.
  
  
  METHODS
  GAAs were IL13Rα2, EphA2, WT1, and Survivin. Synthetic peptides were emulsified in Montanide-ISA-51 and given every 3 weeks for eight courses with intramuscular injections of poly-ICLC, followed by q12 week booster vaccines.
  
  
  RESULTS
  Cohorts 1, 2, and 3 enrolled 12, 1, and 10 patients, respectively. No regimen-limiting toxicity was encountered except for one case with grade 3 fever, fatigue, and mood disturbance (cohort 1). ELISPOT assays demonstrated robust IFNγ responses against at least three of the four GAA epitopes in 10 and 4 cases of cohorts 1 and 3, respectively. Cohort 1 patients demonstrated significantly higher IFNγ responses than cohort 3 patients. Median progression-free survival (PFS) periods since the first vaccine are 17 months in cohort 1 (range, 10-47+) and 12 months in cohort 3 (range, 3-41+). The only patient with large astrocytoma in cohort 2 has been progression-free for more than 67 months since diagnosis.
  
  
  CONCLUSIONS
  The current regimen is well tolerated and induces robust GAA-specific responses in WHO grade 2 glioma patients. These results warrant further evaluations of this approach. Clin Cancer Res; 21(2); 286-94. ©2014 AACR.
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Surgical Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. OkadaH@neurosurg.ucsf.edu.
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Aki
authors.initials: A
authors.lastname: Hoji
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sakaki
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ahn
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Gary
authors.initials: G
authors.lastname: Kohanbash
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Engh
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Nduka
authors.initials: N
authors.lastname: Amankulor
authors.affiliation: Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Lively
authors.affiliation: Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Chan
authors.affiliation: Oncovir, Inc., Washington, District of Columbia.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.affiliation: Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Shaw
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Potter
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lieberman
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage; D002266:Carboxymethylcellulose Sodium / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D010865:Pilot Projects; D011070:Poly I-C / Q000008:administration & dosage; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives; D016896:Treatment Outcome; D022223:Vaccines, Subunit / Q000008:administration & dosage
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D022223:Vaccines, Subunit; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C