Autologous heat shock protein peptide vaccination for newly diagnosed glioblastoma: Impact of peripheral PD-L1 expression on response to therapy

Orin Bloch, Michael Lim, Michael E. Sughrue, Ricardo J Komotar, John M. Abrahams, Donald M. O'Rourke, Anthony D'Ambrosio, Jeffrey N. Bruce, Andrew T. Parsa

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 ¼ 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.

Original languageEnglish (US)
Pages (from-to)3575-3584
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number14
DOIs
StatePublished - Jul 15 2017

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Glioblastoma
Heat-Shock Proteins
Vaccination
Peptides
Survival
Vaccines
Confidence Intervals
temozolomide
Myeloid Cells
Immunosuppression
Radiotherapy
Therapeutics
Prophages
Circulating Neoplastic Cells
Karnofsky Performance Status
Drug Therapy
Neoplasms
Phase II Clinical Trials
Proportional Hazards Models
Methylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Autologous heat shock protein peptide vaccination for newly diagnosed glioblastoma : Impact of peripheral PD-L1 expression on response to therapy. / Bloch, Orin; Lim, Michael; Sughrue, Michael E.; Komotar, Ricardo J; Abrahams, John M.; O'Rourke, Donald M.; D'Ambrosio, Anthony; Bruce, Jeffrey N.; Parsa, Andrew T.

In: Clinical Cancer Research, Vol. 23, No. 14, 15.07.2017, p. 3575-3584.

Research output: Contribution to journalArticle

Bloch, Orin ; Lim, Michael ; Sughrue, Michael E. ; Komotar, Ricardo J ; Abrahams, John M. ; O'Rourke, Donald M. ; D'Ambrosio, Anthony ; Bruce, Jeffrey N. ; Parsa, Andrew T. / Autologous heat shock protein peptide vaccination for newly diagnosed glioblastoma : Impact of peripheral PD-L1 expression on response to therapy. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 14. pp. 3575-3584.
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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 ¼ 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.",
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T1 - Autologous heat shock protein peptide vaccination for newly diagnosed glioblastoma

T2 - Impact of peripheral PD-L1 expression on response to therapy

AU - Bloch, Orin

AU - Lim, Michael

AU - Sughrue, Michael E.

AU - Komotar, Ricardo J

AU - Abrahams, John M.

AU - O'Rourke, Donald M.

AU - D'Ambrosio, Anthony

AU - Bruce, Jeffrey N.

AU - Parsa, Andrew T.

PY - 2017/7/15

Y1 - 2017/7/15

N2 - 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 ¼ 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.

AB - 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 ¼ 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.

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