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Abstract Details

AbstractDetails

Abstract Date: 5/1/2016

Author(s):
Kristen A. Batich
Elizabeth Reap, PhD
Gary Archer, PhD
Luis Sanchez Perez, PhD
Pam Norberg, BS
Robert Schmittling, BS
Weihua Xie, MS
James Herndon II, PhD
Patrick Healy, MS
Duane Mitchell, MD, PhD
John Sampson, MD, PhD (Durham, NC)

Introduction

Cytomegalovirus (CMV) antigens are expressed in a high proportion of glioblastomas (GBMs) and could serve as tumor-specific targets for immunotherapy.


Methods

In a randomized and blinded trial, patients with primary GBM received standard radiation and temozolomide (TMZ) (200 mg/m2 x 5 days) combined with a dendritic cell (DC) vaccine pulsed with mRNA encoding the CMV antigen pp65 and vaccine site pre-conditioning consisting of either tetanus-diphtheria (Td) toxoid or unpulsed DCs. In a subsequent single arm Phase II trial, patients received dose-intensified TMZ (100 mg/m2 x 21 days) and pp65-DCs admixed with GM-CSF. Both trials assessed immunogenicity by pp65-specific ELISpot, progression-free survival (PFS), and overall survival (OS).


Results

Patients receiving pp65-DCs and Td pre-conditioning showed a significant increase in both PFS and OS (p=0.013; median PFS=15.4 months; median OS=25.7 months) compared to patients receiving unpulsed DCs who had median PFS and OS of 10.8 and 18.5 months, respectively. Three censored patients from the Td cohort did not progress and were alive at the time of survival analysis (>41.1 months). The survival benefit of pp65 DC vaccines was confirmed in a second trial, wherein patients given pp65-DCs demonstrated increased pp65-specific immune responses (p=0.0186). PFS and OS were also significantly increased (median PFS=25.3 months, CI95: 11.0-undefined; median OS=41.1 months, CI95: 21.6-undefined). Four of 11 patients remain progression-free at 59-64 months from diagnosis. For both trials, there was no trend across prognostic factors (age, KPS, IDH-1/2 mutation, and MGMT promoter methylation) that could provide a more favorable outcome. 

Conclusion:

In two separate trials, including one blinded and randomized trial, targeting CMV in GBM significantly increased patient survival and generated potent immune responses compared to controls. CMV pp65-DC vaccines have now been associated with superior OS rates in multiple trials, fortifying the rationale for CMV targeting and long-term survival in other studies. 

Keywords:

Article ID: AA-34825


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