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Principal Investigator: John Tanner Wilson
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2024
Award: $346,493
Funding agency: National Cancer Institute
PROJECT SUMMARY
Immune checkpoint blockade (ICB) is an immunotherapy that is revolutionizing cancer treatment, but is
effective in a minority of patients. Across many cancer types, this can largely be ascribed to an insufficient
number or function of tumor infiltrating T cells positioned for reactivation by ICB antibodies. Therefore, there is
a critical need for strategies to increase tumor immunogenicity that results in a greater number of patients that
benefit from immunotherapy. Our long-term research goal is to improve responses to immunotherapy through
the molecular engineering of materials that harness endogenous mechanisms of antitumor innate immunity. To
that end, we have developed STING-activating nanoparticles (STING-NPs) – a new class of endosome-
destabilizing polymer vesicles (polymersomes) that enhance the cytosolic delivery of cyclic dinucleotide (CDN)
agonists of the stimulator of interferon genes (STING) pathway. CDNs have poor drug-like properties and
therefore suffer from poor cellular targeting, rapid clearance, and inefficient transport to the cytosol
where STING is localized. This has restricted clinical evaluation of CDNs to local, intratumoral administration,
which is not feasible for many cancer patients with advanced disseminated disease. STING-NPs enhance the
potency of CDNs by several orders of magnitude, resulting in increased tumor immunogenicity, inhibition of
tumor growth, and improved response to ICB. Our objective in this R01 application is to further expand the
utility and therapeutic window of STING-NPs by 1) optimizing their properties for safe and effective systemic
administration via an intravenous route, and 2) designing new combination therapies that leverage their
immunopharmacological properties to improve immunotherapy responses in melanoma models that are
resistant to ICB. We will accomplish this through the following Specific Aims. First, we will re-engineer the
polymersome corona to optimize the pharmacokinetics and biodistribution profile of intravenously administered
STING-NP to achieve maximal CDN delivery and STING activation in the tumor microenvironment. Second,
we will synthesize a new class of modified CDNs that are structurally optimized for increased incorporation and
retention into STING-NPs, and will investigate the effect of CDN structure, loading, and stability on
immunostimulatory activity and therapeutic efficacy. Third, we will develop rationally designed and clinically
relevant chemo- and immunotherapy combinations that target mechanisms of resistance to STING agonists
that we have recently identified. Overall, these studies will advance STING-NPs as a platform for increasing
tumor immunogenicity and improving outcomes of immunotherapy. In doing so, these investigations will also
advance our understanding of relationships between nanocarrier properties, pharmacological behavior,
antitumor immunity, therapeutic activity, and toxicity with potential to inform design criteria that are broadly
applicable to STING and other innate immune agonists.
Terms: <Address><Affinity><Agonist><Antibodies><B7-H3><B7H3><Behavior><Biodistribution><Biological><CD276><CD276 gene><Cancer Patient><Cancer Treatment><Checkpoint inhibitor><Circulation><Clinical><Clinical Evaluation><Clinical Testing><Clinical Treatment><Combination immunotherapy><Cross-Priming><Cyclicity><Cytosol><Development><Dinucleoside Phosphates><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Precursors><Drugs><Endosomes><Engineering><Gene Activation><Generations><Goals><Half-Life><Immune><Immune Cell Activation><Immune checkpoint inhibitor><Immune mediated therapy><Immune memory><Immune response><Immunes><Immunologic Memory><Immunological Memory><Immunological response><Immunologically Directed Therapy><Immunooncology><Immunotherapeutic agent><Immunotherapy><Infiltration><Innate Immunity><Intravenous><Investigation><Ligands><Lipids><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Medication><Medicinal Chemistry><Melanoma><Mice><Mice Mammals><Minority><Modeling><Molecular><Murine><Mus><Myeloid-derived suppressor cells><Nanotechnology><Native Immunity><Natural Immunity><Nature><Non-Specific Immunity><Nonspecific Immunity><Pathway interactions><Patients><Periodicity><Pharmaceutic Chemistry><Pharmaceutical Agent><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Phosphodiesterases><Polymers><Population><Position><Positioning Attribute><Pro-Drugs><Prodrugs><Property><Publishing><Receptosomes><Recurrent disease><Regimen><Relapsed Disease><Research><Resistance><Rhythmicity><Route><Science><Sentinel Lymph Node><Sentinel Node><Stimulator of Interferon Genes><Structure><Structure-Activity Relationship><T-Cells><T-Lymphocyte><T-cell inflamed><Therapeutic><Therapeutic Uses><Toxic effect><Toxicities><Treatment Efficacy><Tumor Antigens><Tumor Immunity><Tumor-Associated Antigen><Tumor-infiltrating immune cells><Up-Regulation><Upregulation><Vesicle><anamnestic reaction><anti-cancer immunotherapy><anti-cancer therapy><anti-tumor immunity><anticancer immunotherapy><antitumor immunity><biologic><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cancer antigens><cancer immunity><cancer immunology><cancer immunotherapy><cancer infiltrating T cells><cancer microenvironment><cancer therapy><cancer type><cancer-directed therapy><cellular targeting><check point blockade><checkpoint blockade><chemical structure function><clinical relevance><clinical test><clinical translation><clinically relevant><clinically translatable><combinatorial immunotherapy><cyclic GMP-AMP synthase/STING><design><designing><developmental><dinucleotide><drug/agent><dual immunotherapy><engineered immune system><host response><immune activation><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point><immune check point blockade><immune check point inhibitor><immune checkpoint><immune checkpoint blockade><immune drugs><immune engineering><immune resistance><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapeutics><immune-based therapies><immune-based treatments><immune-oncology><immune-resistant><immunecheckpoint><immuno oncology><immuno therapy><immunoengineering><immunogenicity><immunologic therapeutics><immunology oncology><immunoresistance><immunoresponse><immunosuppressive myeloid cells><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><improved><improved outcome><infiltration of tumors by immune cells><innovate><innovation><innovative><insight><intervention efficacy><intratumoral immune cell><intratumoral immune infiltrate><intravenous administration><multidisciplinary><myeloid suppressor cells><myeloid-derived suppressive cells><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanocarrier><nanoparticle><nanosized particle><nanotech><nanotechnological><nanovessel><neoplasm immunology><new approaches><new combination therapies><novel><novel approaches><novel strategies><novel strategy><oncoimmunology><pathway><pharmaceutical><pharmacologic><phosphoric diester hydrolase><polymer><polymeric><pre-clinical development><preclinical development><rational design><recruit><research clinical testing><resistance mechanism><resistant><resistant mechanism><response><response to therapy><response to treatment><restraint><secondary immune response><small molecular inhibitor><small molecule inhibitor><structure function relationship><success><suppressive myeloid cells><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic response><therapeutic target><therapy efficacy><therapy response><thymus derived lymphocyte><treatment response><treatment responsiveness><trial regimen><trial treatment><tumor><tumor growth><tumor immune cell><tumor immune infiltrate><tumor immunology><tumor infiltrating T cells><tumor infiltration of immune cells><tumor microenvironment><tumor-specific antigen><uptake>