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Principal Investigator: CHAD A. MIRKIN
Organization: NORTHWESTERN UNIVERSITY
Fiscal Year: 2024
Award: $490,839
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
This research will utilize spherical nucleic acid (SNA) nanostructures to develop effective, structure-informed
vaccines for advanced melanoma. Traditional treatments (i.e. chemotherapy or radiation) are less successful for
melanoma because of difficulties in discerning melanoma cells phenotypically. Immunotherapeutics must ensure
that melanoma—with a high mutational burden—cannot easily evade the immune system. SNAs can function
as robust cancer vaccines through the precise control over the presentation of multiple melanoma-associated
targets to immune cells which lowers its potential for immune evasion. SNAs are composed of a nanoparticle
core with a dense radial shell of nucleic acids. When synthesized using immunostimulatory “adjuvant”
oligonucleotides, SNAs induce immune responses. Indeed, this adjuvant only structure demonstrates the
enhanced responses generated from a 3D structure compared to linear adjuvant and forms the basis of an
ongoing Phase 1b/2 clinical trial. We have exploited the ease of chemical synthesis and modular architecture of
SNAs, and synthesized them to include both adjuvant and a single tumor-associated peptide (“antigen”). These
structures enhance antitumor responses and provide long-term protective immunity in model systems, and in
particular, there is a strong relationship between vaccine structure and efficacy. In our proposed work, we aim
to develop SNA vaccines against melanoma by precisely incorporating and presenting multiple
immunostimulatory cues to the immune system. SNAs will be synthesized with multiple clinically-relevant
melanoma antigens (MHC-I and -II restricted, tumor-associated, neoantigens), with structural variations in how
the adjuvant and antigen are presented. Control over structure, combined with in vitro and in vivo evaluations of
immunostimulation, will elucidate structure-activity relationships that will inform the future of cancer vaccine
design. Using structure to control the presentation of multiple immune system cues has the power to elevate
immune responses to melanoma and improve clinical outcomes. In Aim 1, we will synthesize SNAs containing
multiple antigens and varied stabilities to enhance antigen-specific T cell responses. We will analyze their uptake
by immune cells, subcellular trafficking of the SNA components, and kinetics of activation of multiple pathways
(e.g. antigen presentation, co-stimulatory marker expression). In Aim 2, we will compare different administration
routes and analyze in vivo biodistribution and uptake kinetics, as well as the antigen-specific immune responses
raised by SNAs in immunocompetent mice. We will assess raised responses after delivery of SNAs containing
human antigens to humanized mice and patient specimens. In Aim 3, we will evaluate SNA antitumor efficacy in
vivo alone and in combination with immune checkpoint blockade, and identify SNAs as candidates for further
preclinical studies and clinical translation. Significantly, this approach will generate a structure-based
understanding of SNA performance as vaccines, and improve immunotherapy by generating a breadth of T cell
responses with superior efficacies.
Terms: <3-D structure><3-dimensional structure><3D structure><Adjuvant><Agonist><Animals><Antigen Presentation><Antigen Targeting><Antigen-Presenting Cells><Antigenic Determinants><Antigens><Antineoplastic Vaccine><Antitumor Response><Architecture><B7-H1><B7H1><Binding Determinants><Biodistribution><Biologic Models><Biological Models><CD274><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cancer Treatment><Cancer Vaccines><Cancers><Cell Body><Cells><Chemicals><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy and Radiation><Chemotherapy and/or radiation><Chemotherapy-Oncologic Procedure><Clinic><Clinical><Clinical Evaluation><Clinical Testing><Clinical Treatment><Combination Chemotherapy Regimen><Core Particle><Cresolase><Cues><Development><Disease><Disorder><Dopa Oxidase><Engineering / Architecture><Enhancement Technology><Ensure><Epitopes><Evaluation><Foundations><Future><GP100><Genetic Alteration><Genetic Change><Genetic defect><Goals><Health><Human><Immune><Immune Cell Activation><Immune Evasion><Immune mediated therapy><Immune response><Immune system><Immunes><Immunity><Immunocompetent><Immunologic Stimulation><Immunological Stimulation><Immunological response><Immunologically Directed Therapy><Immunostimulation><Immunostimulatory drug><Immunotherapeutic agent><Immunotherapy><In Vitro><In vivo analysis><Individual><Innate Immune Response><Intravenous><Kinetics><LYT3><ME20><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Melanocyte Protein 17><Melanoma><Melanoma Cell><Melanoma Vaccine><Melanoma patient><Mice><Mice Mammals><Model System><Modeling><Modern Man><Modification><Monophenol Monooxygenase><Mouse Homolog of SILVER><Murine><Mus><Mutation><Nanostructures><Nanotechnology><Neoplasm Vaccines><Nucleic Acid Vaccines><Nucleic Acids><Nucleosome Core><Nucleosome Core Particle><Oligo><Oligonucleotides><Outcome><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><PMEL gene><PMEL protein><PMEL17><Pathway interactions><Patients><Peptides><Performance><Phase 1b/2 Clinical Trial><Phase 1b/2 Trial><Phase 1b/II Clinical Trial><Phase Ib/II Clinical Trial><Phase Ib/II Trial><Phenol Oxidase><Phenoloxidase><Phenotype><Position><Positioning Attribute><Premelanosomal Protein><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proteins><Quimioterapia><Radial><Radiation><Radius><Receptor Protein><Research><Research Specimen><Route><SILV gene><SILV protein><Signal Pathway><Specimen><Spherical Nucleic Acids><Structure><Structure-Activity Relationship><T cell response><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TLR9 gene><TLR9 protein><TLR9 receptor><Technology><Testing><Therapeutic><Translations><Tumor Burden><Tumor Escape><Tumor Immune Escape><Tumor Load><Tumor Vaccines><Tyrosinase><Vaccination><Vaccine Design><Vaccines><Variant><Variation><Work><accessory cell><anti-cancer research><anti-cancer therapy><anti-tumor immune response><anti-tumor response><anti-tumor vaccine><antigen-specific T cells><cancer chemotherapy><cancer evasion><cancer immune escape><cancer immune evasion><cancer microenvironment><cancer research><cancer therapy><cancer-directed therapy><check point blockade><checkpoint blockade><chemical structure function><chemical synthesis><chemo/radiation therapy><chemotherapy and radiotherapy><clinical relevance><clinical test><clinical translation><clinically relevant><clinically translatable><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><design><designing><determine efficacy><developmental><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><genome mutation><host response><humanized mice><humanized mouse><immune activation><immune check point blockade><immune checkpoint blockade><immune competent><immune drugs><immune evasive><immune stimulatory agent><immune stimulatory drug><immune stimulatory therapeutic><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunologic therapeutics><immunoresponse><immunostimulatory agents><immunostimulatory biologics><immunotherapeutics><immunotherapy agent><improved><in vitro testing><in vivo><in vivo Model><in vivo evaluation><in vivo testing><innovate><innovation><innovative><malignancy><melanoma-associated antigen><monophenol oxidase><mouse model><murine model><nano meter scale><nano meter sized><nano particle><nano tech><nano technology><nano-sized particle><nano-sized structures><nano-structures><nano-technological><nanometer scale><nanometer sized><nanoparticle><nanoscale><nanosized particle><nanotech><nanotechnological><nanotherapeutic><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><nucleic acid structure><nucleic acid-based vaccine><oligos><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pre-clinical study><preclinical study><prevent><preventing><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein death-ligand 1><radiation or chemotherapy><rational design><receptor><research clinical testing><response><sle2><stoichiometry><structure function relationship><subcutaneous><subdermal><success><systemic lupus erythematosus susceptibility 2><three dimensional structure><toll-like receptor 9><trafficking><translation><trial regimen><trial treatment><tumor><tumor evasion><tumor immune evasion><tumor microenvironment><uptake><vaccine for cancer>