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Principal Investigator: Peng Zhang
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2023
Award: $358,680
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Radiation therapy (RT) is a key component of standard of care treatments for glioblastoma (GBM), the most
common and deadly primary brain malignancy in adults. Beyond the direct cytotoxic effect on tumor itself, RT-
elicited anti-tumor immune responses have recently been appreciated as a key factor to the treatment outcomes.
These responses are dependent on the functionality of myeloid cells, an essential component of the innate
immune system. However, within tumor microenvironment, much of the myeloid compartment is programed to
be immunosuppressive, which impairs the anti-tumor immune responses and thereby therapeutic effects of RT.
The objective of this proposed work is to harness and reprogram immunosuppressive tumor-associated myeloid
cells (TAMCs), the most abundant immune population in GBM, to amplify the RT-elicited anti-tumor immune
responses. To enable a precise and efficient therapeutic targeting of TAMC, we propose the development of a
bridge-lipid nanoparticle (B-LNP) platform with the ability to actively target the GBM-induced TAMC in-vivo. Our
preliminary data suggest that B-LNP tethers TAMC to GBM through a “bridging” effect and concurrently blocks
the anti-phagocytic effectors used by GBM to escape immune surveillance. This platform also enables TAMC-
targeted delivery of an agonist for stimulator of interferon genes (STING), a key factor in bridging innate and
adaptive anti-tumor immunity, resulting in the tumor displaying a pro-inflammatory phenotype that robustly
stimulates effector T cell infiltration of tumor. In preclinical animal models, our TAMC-targeted reprogramming
promotes brain tumor regression, and increases the anti-tumor activity of RT.
The central hypothesis of this proposal is that nanoparticle therapies that simultaneously activate TAMC
phagocytic activity and interferon pathway signaling will amplify the RT-stimulated anti-tumor immunity against
GBM. We will focus on two different anti-GBM mechanisms of TAMC that our nanoparticle could harness:
phagocytosis of GBM (Aim 1) and activation of effector T cell responses (Aim 2). Lastly, we will determine the
effectiveness of TAMC-targeted therapy in the context of standard of care treatments for GBM (Aim 3). The
feasibility for clinical translation will be thoroughly evaluated using preclinical animal models, including a unique
humanized animal model of GBM, and clinical GBM samples, which will test the effectiveness of a humanized
version of the therapeutics. Overall, our study provides a novel approach to reshape the immunosuppressive
tumor microenvironment responsible for therapy resistance, and promote current standard of care therapies for
GBM.
Terms: <21+ years old><Address><Adult><Adult Human><Agonist><Animal Model><Animal Models and Related Studies><Anti-CD47><Antitumor Response><Brain><Brain Cancer><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><CD47><CD47 Antigen><CD47 Glycoprotein><CD47 gene><Cancer Patient><Cancer Treatment><Cancers><Cell Body><Cells><Clinical><Data><Development><Educational Mainstreaming><Effectiveness><Encephalon><Experimental Animal Model><Gene Activation><Genes><Glioblastoma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Human><IFN><Immune><Immune Surveillance><Immune response><Immunes><Immunochemical Immunologic><Immunologic><Immunologic Surveillance><Immunologic Surveillances><Immunological><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunologically><Immunologics><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunosurveillance><Impairment><Infiltration><Inflammatory><Inflammatory Response><Innate Immune System><Integrin-Associated Protein><Interferons><Knowledge><Laboratories><MER6><Mainstreaming><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Mice><Mice Mammals><Modern Man><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Myeloid-derived suppressor cells><Nanotechnology><Nature><Newly Diagnosed><Pathway interactions><Phagocytes><Phagocytic Cell><Phagocytosis><Phenotype><Play><Population><Radiation therapy><Radiotherapeutics><Radiotherapy><Research><Research Support><Resistance><Role><Route><Sampling><Shapes><Signal Pathway><Stimulator of Interferon Genes><Surface Antigen Identified by Monoclonal Antibody 1D8><T cell infiltration><T cell response><T-Cells><T-Lymphocyte><Teff cell><Temodal><Temodar><Testing><Therapeutic><Therapeutic Effect><Toxic effect><Toxicities><Treatment outcome><Tumor Antigens><Tumor Cell><Tumor Immunity><Tumor Promotion><Tumor-Associated Antigen><Tumor-associated macrophages><Work><achievement Mainstream Education><adulthood><amebocyte><anti-cancer immunotherapy><anti-cancer therapy><anti-tumor effect><anti-tumor immune response><anti-tumor immunity><anti-tumor response><anticancer immunotherapy><anticancer therapy><antitumor effect><antitumor immune response><antitumor immunity><assess effectiveness><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cancer antigens><cancer immunity><cancer immunotherapy><cancer infiltrating T cells><cancer microenvironment><cancer therapy><cancer-directed therapy><clinical relevance><clinical translation><clinically relevant><clinically translatable><cyclic GMP-AMP synthase/STING><cytotoxic><determine effectiveness><developmental><effectiveness assessment><effectiveness evaluation><effectiveness testing><effector T cell><evaluate effectiveness><examine effectiveness><genotoxicity><glioblastoma multiforme><host response><humanized mice><humanized mouse><immune microenvironment><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune-based cancer therapies><immunogenic apoptosis><immunogenic cell death><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive myeloid cells><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><in vivo><interest><lipid based nanoparticle><lipid nanoparticle><malignancy><methazolastone><model of animal><mouse model><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanoparticle therapy><nanosized particle><nanotech><nanotechnological><nanotherapeutic><neoplasm/cancer><neoplastic cell><new approaches><novel approaches><novel strategies><novel strategy><pathway><pre-clinical><preclinical><programs><radiation effect><radiation treatment><resistance to therapy><resistant><resistant to therapy><response><site targeted delivery><social role><spongioblastoma multiforme><standard of care><success><suppressive myeloid cells><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><temozolomide><therapeutic nanoparticles><therapeutic resistance><therapeutic target><therapy resistant><thymus derived lymphocyte><treatment effect><treatment resistance><treatment strategy><treatment with radiation><tumor><tumor immune microenvironment><tumor infiltrating T cells><tumor microenvironment><tumor-immune system interactions><tumor-specific antigen><tumors in the brain>