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Principal Investigator: Connie Wu
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $186,865
Funding agency: National Institute of Biomedical Imaging and Bioengineering
PROJECT SUMMARY: The generation of a robust disease-specific immune response is a critical challenge in
cancer immunotherapies, many of which provide clinical benefit in only a fraction of patients despite remarkable
successes, and in infectious disease vaccines. Harnessing the innate immune system, which has evolved to
sense and respond to complex combinations of pathogen-associated molecular patterns, is highly promising for
augmenting cancer immunotherapies and infectious disease vaccines. While many synthetic innate immune
agonists that activate pattern recognition receptors (PRRs) have been developed as vaccine adjuvants, only a
handful of adjuvants have been clinically approved. Generation of a durable immune response faces key barriers:
(1) many current PRR agonist-based adjuvants rely on a single agonist, poorly recapitulating natural pathogen
recognition by the innate immune system; (2) while mounting evidence shows that combining PRR agonists can
promote synergistic activation, control and understanding of the combinatorial effects and spatial modulation of
multiple agonists remain inadequate; and (3) further exacerbating these gaps is a scarcity of platforms for
precisely tuning combinations and spatial arrangements of innate immune agonists. To address these knowledge
and technological gaps, the proposed work will engineer a molecularly defined, modular “all-in-one”
platform that utilizes RNA as both a multifunctional agonist and scaffold to sculpt the immune response
via (1) precise spatial patterning and multivalency of PRR agonists; (2) combinatorial control of innate immune
signaling pathways; and (3) targeted self-delivery. The first aim will leverage the programmable structural
features and sequence of a modular RNA scaffold to combine and pattern PRR agonists for synergistic innate
immune activation. In an orthogonal aim, the team will exploit the natural immune cell-targeting abilities of fungal
wall polysaccharides to create a bioinspired, “all-in-one” synthetic glyco-RNA that can target and activate
antigen-presenting cells. The translational potential of the developed RNA platform will then be explored in a
proof-of-concept evaluation of in vivo therapeutic efficacy in the third aim, using a syngeneic mouse model of
melanoma. If successful, the proposed work will introduce a new paradigm for the rational design of combinatorial
innate immune agonists and a new class of synthetic glyco-RNA therapeutic molecules for targeted immune
activation. The highly modular platform will enable (1) fundamental studies of how combinations of innate
immune agonists and their spatial arrangements function at the molecular, cellular, and organismal levels; and
(2) precise modulation of disease-specific immune responses for applications in cancer and infectious diseases.
Terms: <ATRA><Address><Adjuvant><Agonist><Antigen-Presenting Cells><Benchmarking><Best Practice Analysis><Bone Marrow><Bone Marrow Reticuloendothelial System><CPG-oligonucleotide><Cancers><Cell Body><Cell Line><Cell Wall><CellLine><Cells><Clinical><Communicable Diseases><Complex><DNA><Dendritic Cells><Deoxyribonucleic Acid><Disease><Disorder><Double-Stranded RNA><Elements><Endowment><Engineering><Ensure><Face><Future><Generations><Genes><Glycans><Immune><Immune Cell Activation><Immune Targeting><Immune response><Immune signaling><Immunes><Immunoactivators><Immunoadjuvants><Immunologic Adjuvants><Immunological response><Immunopotentiators><Immunostimulants><In Vitro><In vivo analysis><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Innate Immune Response><Innate Immune System><Knowledge><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Mannan><Mannans><Melanoma><Modality><Molecular><Nature><Non-Polyadenylated RNA><Pathway interactions><Patients><Pattern><Pattern recognition receptor><Polymers><Polysaccharides><RNA><RNA Gene Products><RNA Viruses><RNA based therapeutics><RNA based therapy><RNA therapy><Receptor Activation><Reporter><Retinoic Acid><Ribonucleic Acid><Route><Signal Pathway><Spinal Column><Spine><Strains Cell Lines><Structure><Structure-Activity Relationship><System><TLR protein><TLR3><TLR3 gene><TLR7><TLR7 gene><Technology><Testing><Therapeutic><Toll-Like Receptor 3><Toll-Like Receptor 7><Toll-Like Receptor Family Gene><Toll-like receptors><Trans Vitamin A Acid><Treatment Efficacy><Tretinoin><Tretinoinum><Tumor Burden><Tumor Load><Vaccine Adjuvant><Vaccines><Veiled Cells><Vertebral column><Vitamin A Acid><Work><accessory cell><all-trans-Retinoic Acid><all-trans-Vitamin A acid><anti-cancer immunotherapy><anti-tumor immune response><anticancer immunotherapy><backbone><benchmark><cancer immunotherapy><chemical structure function><combinatorial><cultured cell line><cytokine><design><designing><dsRNA><faces><facial><host response><immune activation><immune system response><immune-based cancer therapies><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><in situ vaccine><in vivo><in vivo evaluation><in vivo testing><innate immune pathways><intervention efficacy><lipid based nanoparticle><lipid nanoparticle><malignancy><mouse model><multi-modality><multimodality><murine model><neoplasm/cancer><pathogen><pathway><polymer><polymeric><rational design><scaffold><scaffolding><structure function relationship><success><therapeutic RNA><therapeutic efficacy><therapy efficacy><tool><trans-Retinoic Acid><translational opportunities><translational potential><triphosphate><tripolyphosphate><uptake><vaccine efficacy><vaccine for immunotherapy><vaccine immunotherapy><vaccine-based immunotherapy>