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Principal Investigator: JOHN H. SAMPSON
Organization: DUKE UNIVERSITY
Fiscal Year: 2022
Award: $400,950
Funding agency: National Cancer Institute
ABSTRACT
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.
Terms: <Abscission><Adjuvant><Antigens><Antineoplastic Vaccine><Assay><Bioassay><Biologic Assays><Biological Assay><Blinded><Brain><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><CCL3><CCL3 gene><CMV><Cancer Cause><Cancer Etiology><Cancer Vaccines><Cell Body><Cell Locomotion><Cell Migration><Cell Movement><Cells><Cellular Migration><Cellular Motility><Chemokine (C-C motif) Ligand 3><Clinical><Clinical Research><Clinical Study><Cytomegalovirus><Data><Dendritic Cells><Dermatologic Body System><Dermatologic Organ System><Development><Diphtheria><Diphtheria Toxoid><Diphtheria Vaccine><Dose><EC 2.1.1><Encephalon><Enrollment><Environment><Excision><Extirpation><G0S19-1><GM-CSF><Genetic Markers><Glioblastoma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Granulocyte-Macrophage Colony-Stimulating Factor><HCMV><Histamine-Producing Cell-Stimulating Factor><Human><Immune response><Immunological response><Inactivated Vaccines><Inactivated Virus Vaccine><Infection><Integument><Integumentary system><Killed Vaccines><LD78ALPHA><Laboratories><Laboratory Study><Ligands><MIP 1alpha><MIP-1-alpha><MIP-1a><MIP1A><Measures><Messenger RNA><Methyltransferase><Mice><Mice Mammals><Modern Man><Molgramostin><Motility><Murine><Mus><Nature><Neoplasm Vaccines><Newly Diagnosed><Nucleic Acids><Operative Procedures><Operative Surgical Procedures><Outcome><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Performance><Phase><Phosphoproteins><Physiologic pulse><Population><Prevention><Primary Brain Neoplasms><Primary Brain Tumors><Production><Progression-Free Survivals><Prophylactic treatment><Prophylaxis><Proteins><Pulse><Radiation><Radiation Dose><Radiation Dose Unit><Radiation therapy><Radiotherapeutics><Radiotherapy><Randomized><Regimen><Removal><Reporting><SCYA3><Salivary Gland Viruses><Sampling><Series><Site><Small Inducible Cytokine A3><Stem Cell Inhibitor><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><T cell response><T-Cells><T-Lymphocyte><TC-GM-CSF><Temodal><Temodar><Tetanus><Tumor Vaccines><Tumor-Cell Human GM Colony-Stimulating Factor><Vaccination><Vaccinee><Vaccines><Veiled Cells><Viral><Viral Antigens><Viral Latency><Virus><Virus Latency><adult youth><anti-tumor immune therapy><anti-tumor immunotherapy><anti-tumor vaccine><antitumor immune therapy><antitumor immunotherapy><antitumor vaccine><cancer death in children><cancer mortality in children><cancer related death in children><cell motility><chemotherapy><childhood cancer death><childhood cancer mortality><clostridial tetanus><cohort><conditioning><conventional therapy><conventional treatment><cytomegalovirus group><dendritic cell vaccination><developmental><draining lymph node><effective therapy><effective treatment><enroll><genetic biomarker><glioblastoma multiforme><granulocyte macrophage colony stimulating factor><host response><immune system response><immunogen><immunogenic><immunoresponse><immunosuppressed><improved><latent infection><mRNA><methazolastone><methylase><neoplasm immunotherapy><novel><phase 2 trial><phase 3 trial><phase II trial><phase III trial><preconditioning><predict survival><predicting response><prediction of response><predictive biomarkers><predictive marker><predictive molecular biomarker><predictive response><predictor of response><predictor of survival><prevent><preventing><radiation treatment><randomisation><randomization><randomly assigned><regional lymph node><resection><response prediction><spongioblastoma multiforme><standard of care><surgery><survival prediction><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><temozolomide><therapeutic vaccine><thymus derived lymphocyte><transmethylase><treatment vaccines><treatment with radiation><tumor><tumor immune therapy><tumor immunotherapy><tumors in the brain><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccine efficacy><vaccine for cancer><vaccine for the treatment><vaccine for treatment><virus antigen><young adult><young adulthood>