We have previously reported in Nature that patients with newly-diagnosed glioblastoma (GBM) randomized to receiving vaccines against Cytomegalovirus (CMV) using a potent vaccine site preconditioning regimen had a statistically significant increase in progression-free survival (PFS) and overall survival (OS). Half of the patients treated this way were still alive nearly 5 years later despite having no genetic markers predicting long-term survival. These results have been repeated in an additional cohort which showed a median survival of 44.1 months with ~36% of patients alive at 5 years. These results are remarkable because GBM remains uniformly lethal with a median OS of < 21 months despite surgical resection, high dose radiation therapy, chemotherapy, and tumor-treating fields, and only 10% of patients typically live past 5 years. In addition to demonstrating the potential for efficacy, our preliminary clinical and laboratory studies demonstrated that preconditioning the vaccination site with tetanus/diphtheria (Td) recall antigens increased DC migration to the draining lymph nodes (DLNs), which predicted PFS and OS as did the production of polyfunctional, CMV-specific T cells. These T cell responses were enhanced by GM-CSF at the vaccine site and pre-vaccination lymphodepletion with standard of care (SOC) temozolomide (TMZ), but inhibited by subsequent adjuvant doses of TMZ. Moreover, mechanistic studies in mice and humans revealed that efficacy was also dependent on producing high systemic levels of the chemokine (C-C motif) ligand 3 (CCL3). We believe these results warrant confirmation in a larger series of patients.
Our Specific Aims are: 1. To conduct a larger Phase 2 trial of CMV pp65-loaded DC vaccination in patients with GBM. Patients with CMV positive, newly diagnosed GBM will receive serial vaccines with CMV pp65-loaded DCs with GM-CSF and Td vaccine site preconditioning. GM-CSF and Td vaccine site preconditioning will be employed because they have been shown to enhance DC migration and increase polyfunctional T cell responses in prior studies. TMZ will be given prior to vaccination to induce homeostatic proliferation of the vaccine-induced T cell responses but not given subsequently to prevent killing of vaccine-induced T cells. 2. To confirm predictors of survival. In our prior studies DC migration to draining lymph nodes, systemic and local CCL3, and CMV pp65-specific polyfunctional T cells predicted PFS and OS. Here we will collect samples to confirm these predictors.

Public Health Relevance

Glioblastoma, the most common form of primary brain tumors, remains uniformly lethal with conventional treatments and is the most frequent cause of cancer death in children and young adults. In studies with limited patient numbers we have recently shown that a vaccine treatment using the patient's own cells and parts of the virus CMV may be effective treatment for these fatal illnesses. We now wish to do a larger study to confirm these results.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA235612-02
Application #
9830603
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Timmer, William C
Project Start
2018-12-01
Project End
2023-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Duke University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705