Antigen-specific immunoreactivity and clinical outcome following vaccination with glioma-associated antigen peptides in children with recurrent high-grade gliomas: results of a pilot study.
Recurrent high-grade gliomas (HGGs) of childhood have an exceedingly poor prognosis with current therapies. Accordingly, new treatment approaches are needed. We initiated a pilot trial of vaccinations with peptide epitopes derived from glioma-associated antigens (GAAs) overexpressed in these tumors in HLA-A2+ children with recurrent HGG that had progressed after prior treatments. Peptide epitopes for three GAAs (EphA2, IL13Rα2, survivin), emulsified in Montanide-ISA-51, were administered subcutaneously adjacent to intramuscular injections of poly-ICLC every 3 weeks for 8 courses, followed by booster vaccines every 6 weeks. Primary endpoints were safety and T-cell responses against the GAA epitopes, assessed by enzyme-linked immunosorbent spot (ELISPOT) analysis. Treatment response was evaluated clinically and by magnetic resonance imaging. Twelve children were enrolled, 6 with glioblastoma, 5 with anaplastic astrocytoma, and one with malignant gliomatosis cerebri. No dose-limiting non-CNS toxicity was encountered. ELISPOT analysis, in ten children, showed GAA responses in 9: to IL13Rα2 in 4, EphA2 in 9, and survivin in 3. One child had presumed symptomatic pseudoprogression, discontinued vaccine therapy, and responded to subsequent treatment. One other child had a partial response that persisted throughout 2 years of vaccine therapy, and continues at >39 months. Median progression-free survival (PFS) from the start of vaccination was 4.1 months and median overall survival (OS) was 12.9 months. 6-month PFS and OS were 33 and 73 %, respectively. GAA peptide vaccination in children with recurrent malignant gliomas is generally well tolerated, and has preliminary evidence of immunological and modest clinical activity.
Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. ian.pollack@chp.edu.|Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh, 4401, Penn Avenue, Pittsburgh, PA, 15224, USA. ian.pollack@chp.edu.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. ian.pollack@chp.edu.
Ian F
IF
Pollack
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Regina I
RI
Jakacki
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Lisa H
LH
Butterfield
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Ronald L
RL
Hamilton
Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Ashok
A
Panigrahy
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Daniel P
DP
Normolle
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Angela K
AK
Connelly
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Sharon
S
Dibridge
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Gary
G
Mason
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Theresa L
TL
Whiteside
Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Neurosurgery, University of California, San Francisco, CA, USA.
Hideho
H
Okada
D000293:Adolescent; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology*; D001932:Brain Neoplasms / Q000276:immunology* / Q000628:therapy*; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives; D002648:Child; D002675:Child, Preschool; D005260:Female; D005910:Glioma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D007223:Infant; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000276:immunology; D053661:Interleukin-13 Receptor alpha1 Subunit; D008297:Male; D010455:Peptides / Q000276:immunology; D010865:Pilot Projects; D011070:Poly I-C / Q000276:immunology; D011107:Polylysine / Q000031:analogs & derivatives / Q000276:immunology; D036104:Receptor, EphA2 / Q000737:chemistry / Q000276:immunology; D053660:Receptors, Interleukin-13 / Q000737:chemistry / Q000276:immunology; D000077022:Survivin; D016896:Treatment Outcome; D055815:Young Adult
D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; C508181:IL13RA1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D053661:Interleukin-13 Receptor alpha1 Subunit; D010455:Peptides; D053660:Receptors, Interleukin-13; D000077022:Survivin; D011107:Polylysine; C019531:poly ICLC; D036104:Receptor, EphA2; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C
Astrocytoma; Glioma; Immunotherapy; Pediatric brain tumor; Vaccine therapy