Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination
Kristen A Batich, Elizabeth A Reap, Gary E Archer, Luis Sanchez-Perez, Smita K Nair, Robert J Schmittling, Pam Norberg, Weihua Xie, James E Herndon 2nd, Patrick Healy, Roger E McLendon, Allan H Friedman, Henry S Friedman, Darell Bigner, Gordana Vlahovic, Duane A Mitchell, John H Sampson, Kristen A Batich, Elizabeth A Reap, Gary E Archer, Luis Sanchez-Perez, Smita K Nair, Robert J Schmittling, Pam Norberg, Weihua Xie, James E Herndon 2nd, Patrick Healy, Roger E McLendon, Allan H Friedman, Henry S Friedman, Darell Bigner, Gordana Vlahovic, Duane A Mitchell, John H Sampson
Abstract
Purpose: Patients with glioblastoma have less than 15-month median survival despite surgical resection, high-dose radiation, and chemotherapy with temozolomide. We previously demonstrated that targeting cytomegalovirus pp65 using dendritic cells (DC) can extend survival and, in a separate study, that dose-intensified temozolomide (DI-TMZ) and adjuvant granulocyte macrophage colony-stimulating factor (GM-CSF) potentiate tumor-specific immune responses in patients with glioblastoma. Here, we evaluated pp65-specific cellular responses following DI-TMZ with pp65-DCs and determined the effects on long-term progression-free survival (PFS) and overall survival (OS).Experimental Design: Following standard-of-care, 11 patients with newly diagnosed glioblastoma received DI-TMZ (100 mg/m2/d × 21 days per cycle) with at least three vaccines of pp65 lysosome-associated membrane glycoprotein mRNA-pulsed DCs admixed with GM-CSF on day 23 ± 1 of each cycle. Thereafter, monthly DI-TMZ cycles and pp65-DCs were continued if patients had not progressed.Results: Following DI-TMZ cycle 1 and three doses of pp65-DCs, pp65 cellular responses significantly increased. After DI-TMZ, both the proportion and proliferation of regulatory T cells (Tregs) increased and remained elevated with serial DI-TMZ cycles. Median PFS and OS were 25.3 months [95% confidence interval (CI), 11.0-∞] and 41.1 months (95% CI, 21.6-∞), exceeding survival using recursive partitioning analysis and matched historical controls. Four patients remained progression-free at 59 to 64 months from diagnosis. No known prognostic factors [age, Karnofsky performance status (KPS), IDH-1/2 mutation, and MGMT promoter methylation] predicted more favorable outcomes for the patients in this cohort.Conclusions: Despite increased Treg proportions following DI-TMZ, patients receiving pp65-DCs showed long-term PFS and OS, confirming prior studies targeting cytomegalovirus in glioblastoma. Clin Cancer Res; 23(8); 1898-909. ©2017 AACR.
Conflict of interest statement
Disclosure of Potential Conflicts of Interest
J.H. Sampson holds stock ownership and is on the Board of Directors with Annias Immunotherapeutics, serves as a consultant and advisory board member for Celldex Therapeutics, and reports honoraria for Celldex Therapeutics, Bristol-Myers Squibb, and Brainlab. D.A. Mitchell is a consultant for Schering Plough North American Investigators Advisory Board. S.K Nair is a co-inventor on a patent that has been licensed by Argos Therapeutics (Durham, NC) through Duke University. S.K. Nair has no financial interests in Argos Therapeutics and is not compensated by Argos Therapeutics. JH. Sampson and D.A. Mitchell are co-inventors on a patent describing the immunologic targeting of CMV antigens in cancer. J.H. Sampson, D.A. Mitchell, and K.A. Batich are co-inventors on a patent for improving the immunogenicity of dendritic cell vaccines. No other potential conflicts of interest were disclosed by the other authors.
©2017 American Association for Cancer Research.
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Source: PubMed