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Principal Investigator: Annick Desjardins
Organization: DUKE UNIVERSITY
Fiscal Year: 2022
Award: $564,267
Funding agency: National Cancer Institute
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.
Terms: <AIDS><Abscission><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunologic Deficiency Syndrome><Alpha Interleukin 2 Receptor><Antibodies><Antigens><Antineoplastic Vaccine><Assay><Bioassay><Biologic Assays><Biological Assay><Biological Response Modifiers><Biomodulators><Blinded><Blood Serum><Brain><Brain Cancer><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><C Chemokines><CCL3><CCL3 gene><CD25><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CMV><CMV vaccine><Cancer Vaccines><Cancers><Cell Locomotion><Cell Migration><Cell Movement><Cellular Migration><Cellular Motility><Chemokine (C-C motif) Ligand 3><Clinical><Clinical Treatment Moab><Cytomegalovirus><Cytomegalovirus Vaccines><Data><Dendritic Cell Vaccine><Dendritic Cells><Dermatologic Body System><Dermatologic Organ System><Diphtheria><Diphtheria Toxoid><Diphtheria Vaccine><Dose><Encephalon><Excision><Experimental Therapies><Extirpation><G0S19-1><Genetic Markers><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><HCMV><High Affinity Interleukin-2 Receptor><Human><IL-2 Receptors><IL-2Ralpha><IL-2Rα><IL2 Receptors><IL2R><IL2RA><IL2RA gene><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune response><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Infection><Integument><Integumentary system><Interleukin 2 Receptor><Investigational Therapies><Investigational Treatments><LD78ALPHA><Laboratories><Ligands><Low Affinity Interleukin 2 Receptor><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><MIP 1alpha><MIP-1-alpha><MIP-1a><MIP1A><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Mediating><Memory><Messenger RNA><Methods><Mice><Mice Mammals><Modern Man><Monoclonal Antibodies><Motility><Murine><Mus><Nature><Neoplasm Vaccines><Neuroglial Neoplasm><Neuroglial Tumor><Newly Diagnosed><Nucleic Acids><Operative Procedures><Operative Surgical Procedures><Patients><Physiologic pulse><Pilot Projects><Prevention><Progression-Free Survivals><Prophylactic treatment><Prophylaxis><Proteins><Publishing><Pulse><Radiation Dose><Radiation Dose Unit><Radiation therapy><Radiotherapeutics><Radiotherapy><Randomized><Regimen><Regulatory T-Lymphocyte><Removal><Reporting><Role><SCYA3><Salivary Gland Viruses><Series><Serum><Site><Small Inducible Cytokine A3><Stem Cell Inhibitor><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><T cell response><T-Cell Depletion><T-Cell Growth Factor Receptors><T-Cells><T-Lymphocyte><T-cell depletion therapy><T-lymphocyte depletion therapy><T8 Cells><T8 Lymphocytes><TCGF Receptors><TCGFR><Tetanus><Transgenic Mice><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treg><Tumor Antigens><Tumor Vaccines><Tumor-Associated Antigen><Vaccinated><Vaccination><Vaccines><Veiled Cells><Viral><Viral Antigens><Viral Latency><Virus Latency><alpha-subunit, receptor, interleukin-2><anti-tumor immune therapy><anti-tumor immunotherapy><anti-tumor vaccine><antitumor immune therapy><antitumor immunotherapy><antitumor vaccine><cancer antigens><cell motility><chemotherapy><clostridial tetanus><cohort><combat><cytomegalovirus group><dendritic cell vaccination><draining lymph node><experimental therapeutic agents><experimental therapeutics><gamma-Chemokines><genetic biomarker><glial-derived tumor><glioblastoma multiforme><host response><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunogen><immunogenic><immunogenicity><immunomodulatory biologics><immunoresponse><immunosuppressive activity><immunosuppressive function><improved><innovate><innovation><innovative><interleukin-2Ralpha><latent infection><lymph gland><lymph nodes><lymphnodes><mAbs><mRNA><malignancy><migration><mouse model><murine model><neoplasm immunotherapy><neoplasm/cancer><neuroglia neoplasm><neuroglia tumor><novel><phase 2 trial><phase 3 trial><phase II trial><phase III trial><pilot study><preconditioning><predictive biomarkers><predictive marker><predictive molecular biomarker><radiation treatment><randomisation><randomization><randomly assigned><regional lymph node><regulatory T-cells><resection><response><social role><spongioblastoma multiforme><surgery><thymus derived lymphocyte><treatment with radiation><tumor><tumor immune therapy><tumor immunotherapy><tumor-specific antigen><tumors in the brain><vaccine efficacy><vaccine for cancer><vaccine immune response><vaccine immunogenicity><vaccine response><vaccine responsiveness><vaccine-induced response><virus antigen>