# Project 1: Targeting cytomegalovirus antigens in glioblastoma with regulatory T cell depletion

> **NIH NIH P01** · DUKE UNIVERSITY · 2021 · $631,432

## Abstract

PROJECT SUMMARY – Project 1
We recently reported in Nature that patients with glioblastoma (GBM) randomized to receive a vaccine against
Cytomegalovirus (CMV) major integument protein pp65 using a tetanus/diphtheria (Td) vaccine site
preconditioning regimen had a statistically significant increase in progression-free survival (PFS) and overall
survival (OS) in a small but randomized, blinded, and controlled trial. Half of the patients treated this way were
still alive nearly 5 years later despite only 10% of patients typically surviving past 5 years. We targeted CMV
because many different groups, including our own, had shown that CMV antigens (Ags), like the
immunodominant pp65, are found in GBM, but not surrounding normal brain; this suggests CMV pp65 could be
subverted as a highly immunogenic and often homogeneously expressed target for anti-tumor immunotherapy.
 In our preliminary study, combined with in-depth mechanistic studies in mice, we demonstrated that
preconditioning the vaccination site with Td recall Ags increased DC migration to the draining lymph nodes
(DLNs), which predicted PFS and OS. Mechanistic studies in mice revealed that the antitumor efficacy of these
vaccines was dependent on the vaccinating Ag being present in the tumor, underscoring pp65 as a target in
GBM. Efficacy was also dependent on a Td recall response and high systemic levels of the chemokine (C-C
motif) ligand 3 (CCL3), which was the only immune mediator elevated in mice and patients. We believe these
data warrant confirmation in our proposed Phase 2 trial with a larger series of patients. This will also allow us
to confirm some of the mechanistic findings in human patients.
 However, systemic immunosuppression mediated in part by elevated levels of regulatory T cells (TRegs) in
patients with GBM still likely limits vaccine efficacy. Recently, we and others have demonstrated that a clinical-
grade antibody targeting CD27 specifically depletes TRegs in transgenic mice and humans. We have also
demonstrated that, unlike clinical approaches targeting CD25 to deplete TRegs, that the anti-CD27 antibody
simultaneously increases vaccine-induced immune responses. Moreover, it specifically coordinates CD4+ and
CD8+ T cell responses leading to enhanced vaccine-induced immunogenicity and increased survival in mice
with established orthotopic glioma. Overall, we hypothesize that Td preconditioning will increase DC migration,
systemic CCL3, and OS, and that TRegs will be reduced while CMV vaccine responses are further enhanced
when a novel anti-CD27 mAb is added to this regimen.

## Key facts

- **NIH application ID:** 10246884
- **Project number:** 5P01CA225622-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** JOHN H. SAMPSON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $631,432
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246884

## Citation

> US National Institutes of Health, RePORTER application 10246884, Project 1: Targeting cytomegalovirus antigens in glioblastoma with regulatory T cell depletion (5P01CA225622-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246884. Licensed CC0.

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