title: Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas.
abstract: Low-grade gliomas (LGGs) are the most common brain tumors of childhood. Although surgical resection is curative for well-circumscribed superficial lesions, tumors that are infiltrative or arise from deep structures are therapeutically challenging, and new treatment approaches are needed. Having identified a panel of glioma-associated antigens (GAAs) overexpressed in these tumors, we initiated a pilot trial of vaccinations with peptides for GAA epitopes in human leukocyte antigen-A2+ children with recurrent LGG that had progressed after at least 2 prior regimens.
  
  
  
  Peptide epitopes for 3 GAAs (EphA2, IL-13Rα2, and survivin) were emulsified in Montanide-ISA-51 and administered subcutaneously adjacent to intramuscular injections of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose every 3 weeks for 8 courses, followed by booster vaccines every 6 weeks. Primary endpoints were safety and T-lymphocyte responses against GAA epitopes. Treatment response was evaluated clinically and by MRI.
  
  
  
  Fourteen children were enrolled. Other than grade 3 urticaria in one child, no regimen-limiting toxicity was encountered. Vaccination induced immunoreactivity to at least one vaccine-targeted GAA in all 12 evaluable patients: to IL-13Rα2 in 3, EphA2 in 11, and survivin in 3. One child with a metastatic LGG had asymptomatic pseudoprogression noted 6 weeks after starting vaccination, followed by dramatic disease regression with >75% shrinkage of primary tumor and regression of metastatic disease, persisting >57 months. Three other children had sustained partial responses, lasting >10, >31, and >45 months, and one had a transient response.
  
  
  
  GAA peptide vaccination in children with recurrent LGGs is generally well tolerated, with preliminary evidence of immunological and clinical activity.
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Regina I
authors.initials: RI
authors.lastname: Jakacki
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Ashok
authors.initials: A
authors.lastname: Panigrahy
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Normolle
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Angela K
authors.initials: AK
authors.lastname: Connelly
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Sharon
authors.initials: S
authors.lastname: Dibridge
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Gary
authors.initials: G
authors.lastname: Mason
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.affiliation: Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., H.O.); Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania (R.I.J., A.K.C., S.D., G.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (R.L.H., T.L.W.); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B.), Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., H.O.), Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P.), Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania (L.H.B., T.L.W.), University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., A.P., A.K.C., S.D., G.M.); University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (I.F.P., R.I.J., L.H.B., R.L.H., D.P.N., G.M., T.L.W., H.O.); Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (D.P.N.); Department of Neurosurgery, University of CaliforniaSan Francisco, San Francisco, California (H.O.).
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D000293:Adolescent; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D002266:Carboxymethylcellulose Sodium / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D000939:Epitopes; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007223:Infant; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology; D007369:Interferon Inducers / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000276:immunology; D008297:Male; D060787:Neoplasm Grading; D010865:Pilot Projects; D011070:Poly I-C / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D011107:Polylysine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000276:immunology / Q000627:therapeutic use; D036104:Receptor, EphA2 / Q000276:immunology; D000077022:Survivin; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods*
chemical_list: D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; D000939:Epitopes; D051034:Inhibitor of Apoptosis Proteins; D007369:Interferon Inducers; D053663:Interleukin-13 Receptor alpha2 Subunit; D000077022:Survivin; D011107:Polylysine; C019531:poly ICLC; D036104:Receptor, EphA2; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C
keywords: astrocytoma; glioma; immunotherapy; pediatric brain tumor; vaccine therapy