Document text
Principal Investigator: E. Antonio Chiocca
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $2,680,832
Funding agency: National Cancer Institute
Abstract
Glioblastoma (GBM) remains a formidable cancer to treat with only anecdotal examples of long-term survivors.
Recently, immunotherapy has seen multiple successes against various types of cancer, but several recent
clinical trials of this modality in GBM have not been successful. It is evident that two inter-related factors in the
complex immunobiology of GBM have thwarted therapeutic efficacy: the existence of multiple
immunosuppressive mechanisms and the significant lymphodepletion in the GBM microenvironment. The
overarching goal of the Program Project is to address the problem of insufficient T cell activation and marked T
cell attenuation in the GBM microenvironment. We will test the overall hypothesis that promotion of CD8+
and CD4+ T cell functionality can overcome the highly immunosuppressive mechanisms of GBM. A
corollary to this hypothesis is that preclinical and clinical trials of immunotherapy combinations will provide
an effective approach to GBM treatment. We have assembled a highly interactive and interdisciplinary team
of 11 investigators in 4 highly integrated Research Projects, supported by 4 Cores. This team (some of whom
have been working together for more than two decades) brings deep expertise in immunobiology, neuro-
oncology, clinical trials, genomics and computational analyses to mechanistically study these two critical factors.
We plan to study how immune checkpoint blockade can be combined with other T cell activating
immunotherapies both in a clinical trial (Project 1) and in preclinical mouse models (Project 2). We propose to
study novel immunosuppressive pathways in human GBMs based on CD161/ Clec2D (Project 3), IL-27 and
endogenous glucocorticoid signaling (Project 4) and understand how these can be overcome to improve the
anti-tumor function of CD4 and CD8 effector T cells. Core services will provide sophisticated genomic (Core 1),
biocomputational/ biostatistical (Core 2), and mouse modeling/ imaging (Core 3) approaches to these Projects.
This Program Project will thus provide significant mechanistic insights into the immunosuppressive
microenvironment of GBM, into preclinical avenues of how to activate T cells against these tumors and finally
into a novel clinical trial to target personalized GBM neoantigens in humans.
Terms: <Achievement><Achievement Attainment><Address><Attenuated><Biometrics><Biometry><Biostatistics><Brain Neoplasia><Brain Neoplasms><Brain Tumors><CD161><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8B><CD8B1><CD8B1 gene><CDK4><CDK4 gene><Cancers><Cell Body><Cell Communication and Signaling><Cell Division Kinase 4><Cell Signaling><Cells><Clinical><Clinical Trials><Collaborations><Combination Vaccines><Combination immunotherapy><Combined Vaccines><Complex><Computational toolkit><Computer Analysis><Cyclin-Dependent Kinase 4><Data><Dendritic Cell Vaccine><EGFRvIII><Environment><Failure><Genomics><Glioblastoma><Glucocorticoids><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Human><Image><Immune><Immune mediated therapy><Immune response><Immune system><Immunes><Immunobiology><Immunologic Subtyping><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunophenotyping><Immunophysiology><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Intracellular Communication and Signaling><Investigators><KLRB1><KLRB1 gene><Killer Cell Lectin-Like Receptor Subfamily B, Member 1 Gene><LYT3><Long-Term Survivors><Malignant Neoplasms><Malignant Tumor><Methods><Mice><Mice Mammals><Modality><Modeling><Modern Man><Murine><Mus><NKR-P1><NKR-P1A><NKRP1A><Newly Diagnosed><Oncolytic viruses><PD 1><PD-1><PD-1 blockade><PD1><PD1 blockade><PSK-J3><Pathway interactions><Patients><Peptide Vaccines><Peptides><Phase 1b Trial><Phase Ib Trial><R-Series Research Projects><R01 Mechanism><R01 Program><Regulation><Reporting><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Safety><Sampling><Services><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Standardization><T cell infiltration><T memory cell><T-Cell Activation><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Technology><Teff cell><Testing><Treatment Efficacy><Tumor Immunity><Vaccines><aPD-1><aPD1><activate T cells><anti programmed cell death 1><anti-PD-1><anti-PD-1 blockade><anti-PD1><anti-PD1 blockade><anti-cancer><anti-programmed cell death protein 1><anti-tumor immunity><antiPD-1><antiPD1><antitumor immunity><attenuate><attenuates><attenuation><bio-computation><bio-computing><biocomputation><biocomputing><biological signal transduction><cancer immunity><cancer type><check point blockade><check point receptors><checkpoint blockade><checkpoint receptors><clinical applicability><clinical application><clinical translation><clinically translatable><cohort><combinatorial immunotherapy><computational analyses><computational analysis><computational toolbox><computational tools><computational toolset><computer analyses><computerized tools><dual immunotherapy><effector T cell><epidermal growth factor receptor VIII><glioblastoma multiforme><hNKR-P1A><host response><imaging><immune check point blockade><immune checkpoint blockade><immune microenvironment><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunomodulatory><immunophenotype><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapy clinical trials><immunotherapy trials><improved><inhibitor><innovate><innovation><innovative><insight><intervention efficacy><longterm survivors><malignancy><memory T lymphocyte><mouse model><murine model><neo-antigen><neo-antigen vaccine><neo-epitopes><neoantigen vaccine><neoantigens><neoepitopes><neoplasm/cancer><neuro-oncology><neurooncology><novel><palliate><pathway><pre-clinical><pre-clinical trial><preclinical><preclinical trial><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><spongioblastoma multiforme><success><systemic lupus erythematosus susceptibility 2><therapeutic efficacy><therapy efficacy><thymus derived lymphocyte><tumor><tumor immune microenvironment><tumor-immune system interactions><tumors in the brain><αPD-1><αPD1>