title: Autologous Heat Shock Protein Peptide Vaccination for Newly Diagnosed Glioblastoma: Impact of Peripheral PD-L1 Expression on Response to Therapy.
abstract: Purpose:Standard therapy for newly diagnosed glioblastoma (GBM) is surgical resection, followed by concurrent radiotherapy and temozolomide chemotherapy. In this phase II clinical trial, the addition of an autologous heat-shock protein vaccine to standard therapy was evaluated. Tumor-induced immunosuppression, mediated by expression of PD-L1 on tumor and circulating immune cells, may impact the efficacy of vaccination. Expression of PD-L1 on peripheral myeloid cells was evaluated for the first time as a predictor of survival.Experimental Design:In this single arm, phase II study, adult patients with GBM underwent surgical resection followed by standard radiation and chemotherapy. Autologous vaccine (Prophage) was generated from resected tumors and delivered in weekly vaccinations after completion of radiotherapy. The primary endpoint was overall survival.Results:Forty-six patients received the vaccine with a median overall survival of 23.8 months [95% confidence interval (CI), 19.8-30.2]. Median overall survival for patients with high PD-L1 expression on myeloid cells was 18.0 months (95% CI, 10.0-23.3) as compared with 44.7 months (95% CI, incalculable) for patients with low PD-L1 expression (hazard ratio 3.3; 95% CI, 1.4-8.6;P= 0.007). A multivariate proportional hazards model revealed MGMT methylation, Karnofsky performance status, and PD-L1 expression as the primary independent predictors of survival.Conclusions:Vaccination with autologous tumor-derived heat shock proteins may improve survival for GBM patients when combined with standard therapy and warrants further study. Systemic immunosuppression mediated by peripheral myeloid expression of PD-L1 is a recently identified factor that may significantly impact vaccine efficacy.Clin Cancer Res; 23(14); 3575-84. ©2017 AACR.
authors.affiliation: Department of Neurological Surgery, Northwestern University, Chicago, Illinois. orin.bloch@northwestern.edu.
authors.forename: Orin
authors.initials: O
authors.lastname: Bloch
authors.affiliation: Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Lim
authors.affiliation: Department of Neurosurgery, University of Oklahoma, Oklahoma City, Oklahoma.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Sughrue
authors.affiliation: Department of Neurosurgery, University of Miami, Miami, Florida.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Komotar
authors.affiliation: Northern Westchester Hospital, Mount Kisco, New York.
authors.forename: John M
authors.initials: JM
authors.lastname: Abrahams
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Donald M
authors.initials: DM
authors.lastname: O'Rourke
authors.affiliation: The Valley Hospital, Paramus, New Jersey.
authors.forename: Anthony
authors.initials: A
authors.lastname: D'Ambrosio
authors.affiliation: Department of Neurological Surgery, Columbia University, New York, New York.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.affiliation: Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Parsa
mesh_terms: D000328:Adult; D000368:Aged; D060890:B7-H1 Antigen / Q000276:immunology*; D019175:DNA Methylation / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006360:Heat-Shock Proteins / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000276:immunology / Q000627:therapeutic use; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D006360:Heat-Shock Proteins; C105992:PDCD1 protein, human; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D022223:Vaccines, Subunit