title: Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma.
abstract: Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.
authors.affiliation: Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Gary E
authors.initials: GE
authors.lastname: Archer
authors.forename: April
authors.initials: A
authors.lastname: Coan
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Duane A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Raymond
authors.initials: R
authors.lastname: Sawaya
authors.forename: Robert
authors.initials: R
authors.lastname: Schmittling
authors.forename: Weiming
authors.initials: W
authors.lastname: Shi
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000276:immunology* / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D019175:DNA Methylation; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology*; D005260:Female; D005909:Glioblastoma / Q000276:immunology* / Q000628:therapy; D006801:Humans; D006968:Hypersensitivity, Delayed; D007124:Immunoenzyme Techniques; D008231:Lymphopenia / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D000077204:Temozolomide; D016896:Treatment Outcome; D022223:Vaccines, Subunit / Q000627:therapeutic use*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D022223:Vaccines, Subunit; C410723:epidermal growth factor receptor VIII; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D066246:ErbB Receptors; D000077204:Temozolomide