title: Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas.
abstract: OBJECTIVE
  Diffuse brainstem gliomas (BSGs) and other high-grade gliomas (HGGs) of childhood carry a dismal prognosis despite current treatments, and new therapies are needed. Having identified a series of glioma-associated antigens (GAAs) commonly overexpressed in pediatric gliomas, we initiated a pilot study of subcutaneous vaccinations with GAA epitope peptides in HLA-A2-positive children with newly diagnosed BSG and HGG.
  
  
  METHODS
  GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13Rα2), and survivin, and their peptide epitopes were emulsified in Montanide-ISA-51 and given every 3 weeks with intramuscular polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for eight courses, followed by booster vaccinations every 6 weeks. Primary end points were safety and T-cell responses against vaccine-targeted GAA epitopes. Treatment response was evaluated clinically and by magnetic resonance imaging.
  
  
  RESULTS
  Twenty-six children were enrolled, 14 with newly diagnosed BSG treated with irradiation and 12 with newly diagnosed BSG or HGG treated with irradiation and concurrent chemotherapy. No dose-limiting non-CNS toxicity was encountered. Five children had symptomatic pseudoprogression, which responded to dexamethasone and was associated with prolonged survival. Only two patients had progressive disease during the first two vaccine courses; 19 had stable disease, two had partial responses, one had a minor response, and two had prolonged disease-free status after surgery. Enzyme-linked immunosorbent spot analysis in 21 children showed positive anti-GAA immune responses in 13: to IL-13Rα2 in 10, EphA2 in 11, and survivin in three.
  
  
  CONCLUSIONS
  GAA peptide vaccination in children with gliomas is generally well tolerated and has preliminary evidence of immunologic and clinical responses. Careful monitoring and management of pseudoprogression is essential.
authors.affiliation: All authors: University of Pittsburgh, Pittsburgh, PA. ian.pollack@chp.edu.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.affiliation: All authors: University of Pittsburgh, Pittsburgh, PA.
authors.forename: Regina I
authors.initials: RI
authors.lastname: Jakacki
authors.affiliation: All authors: University of Pittsburgh, Pittsburgh, PA.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.affiliation: All authors: University of Pittsburgh, Pittsburgh, PA.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.affiliation: All authors: University of Pittsburgh, Pittsburgh, PA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Panigrahy
authors.affiliation: All authors: University of Pittsburgh, Pittsburgh, PA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Potter
authors.affiliation: All authors: University of Pittsburgh, Pittsburgh, PA.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Connelly
authors.affiliation: All authors: University of Pittsburgh, Pittsburgh, PA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Dibridge
authors.affiliation: All authors: University of Pittsburgh, Pittsburgh, PA.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.affiliation: All authors: University of Pittsburgh, Pittsburgh, PA.
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D000293:Adolescent; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D001932:Brain Neoplasms / Q000276:immunology*; D020295:Brain Stem Neoplasms / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002266:Carboxymethylcellulose Sodium / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004337:Drug Carriers / Q000494:pharmacology; D058501:Enzyme-Linked Immunospot Assay; D000939:Epitopes; D005260:Female; D005910:Glioma / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D016233:Immunotherapy, Active / Q000379:methods*; D007223:Infant; D051034:Inhibitor of Apoptosis Proteins / Q000008:administration & dosage / Q000276:immunology*; D007279:Injections, Subcutaneous; D007369:Interferon Inducers / Q000008:administration & dosage / Q000276:immunology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D053208:Kaplan-Meier Estimate; D008239:Lysine / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008297:Male; D011070:Poly I-C / Q000008:administration & dosage / Q000276:immunology*; D036104:Receptor, EphA2 / Q000008:administration & dosage / Q000276:immunology*; D053660:Receptors, Interleukin-13 / Q000008:administration & dosage / Q000276:immunology*; D000077022:Survivin; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; D019496:Cancer Vaccines; D004337:Drug Carriers; D000939:Epitopes; C508181:IL13RA1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D007369:Interferon Inducers; D053661:Interleukin-13 Receptor alpha1 Subunit; D053660:Receptors, Interleukin-13; D000077022:Survivin; D036104:Receptor, EphA2; D008239:Lysine; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C