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Principal Investigator: Rachel Riley
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2020
Award: $9,473
Funding agency: National Cancer Institute
PROJECT SUMMARY
Recent advances in genome sequencing has enabled the detection of random somatic mutations, or
neoantigens, in cancer cells from individual patient samples. Thus, neoantigens are ideal targets for
cancer vaccination because they avoid harmful toxicities to healthy cells, and they are personalized
based on patient samples. For successful vaccination, mRNA molecules need to be delivered to
dendritic cells in the lymph nodes and spleen, which then present the antigen to T cells. This results in
antigen-specific T cell activation that enables them to recognize cancer cells expressing the neoantigen
of interest. However, the use of mRNA for vaccination is limited by molecular instability, in vivo delivery
barriers, and insufficient T cell activation. The main goal of this proposal is to develop lipid nanoparticles
(LNPs) to deliver neoantigen mRNA vaccines to DCs in vivo. LNPs improve upon mRNA delivery by
protecting the molecules from degradation, enabling their cellular uptake, and providing tissue- and
cell-specific accumulation. However, it is not well understood how LNP chemical composition and
physical properties influence mRNA delivery to the lymph nodes, spleen, and to specific immune cell
populations. Developing LNPs specifically for mRNA delivery is challenging because (i) only one LNP
can be evaluated in a mouse at a time, and (ii) results evaluating cellular uptake of LNPs in vitro does
not indicate in vivo results. This proposal will utilize high throughput molecular barcoding technology to
screen a library of LNPs simultaneously in a single mouse. This will enable us to identify key
structure:function relationships between LNP design and delivery, and it will provide LNPs that elicit
strong immune responses for neoantigen vaccine delivery. Thus, I hypothesize that molecular
barcoding will predict the LNP designs that yield the strongest antigen-specific T cell responses to treat
cancer. In Aim 1, I will develop and evaluate molecular barcoding nanotechnology to assess LNP
delivery to immune cells, and particular subtypes of dendritic cells, in the lymph nodes and spleens in
vivo. In Aim 2, I will use the top-performing LNPs to deliver neoantigen vaccines and elicit the
maturation of dendritic cells and activation of T cells to treat a mouse model of colon cancer. Moving
forward, these highly modular platforms can be used to deliver multiple neoantigen mRNAs
simultaneously, and they can be used as tools for studying the underlying immunobiology of specific
populations of immune cells towards improving cancer vaccination.
Terms: <Antigen Targeting><Antigens><Antineoplastic Vaccine><Autoimmune Status><Autoimmunity><Bar Codes><Binding><Body Tissues><Cancer Treatment><Cancer Vaccines><Cancers><Cell Body><Cell Death><Cell Maturation><Cell-Mediated Lympholytic Cells><Cells><Charge><Chemicals><Clinical><Colon Cancer><Colon Carcinoma><Colonic Carcinoma><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><DNA><Dendritic Cells><Dendritic cell activation><Deoxyribonucleic Acid><Detection><Drug Delivery><Drug Delivery Systems><Encapsulated><Genetic Alteration><Genetic Change><Genetic defect><Goals><High Throughput Assay><Immune><Immune Tolerance><Immune response><Immunes><Immunobiology><Immunologic Tolerance><Immunological response><Immunology><Immunophysiology><In Vitro><Injections><Length><Libraries><Lipids><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Macrogols><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Messenger RNA><Mice><Mice Mammals><Molecular><Molecular Interaction><Murine><Mus><Mutation><Nanotechnology><Neoplasm Vaccines><Nucleic Acid Vaccines><Patients><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polyoxyethylenes><Population><Postdoc><Postdoctoral Fellow><Property><RNA vaccine><Research Associate><Sampling><Site><Somatic Mutation><Specificity><Spleen><Spleen Reticuloendothelial System><Structure-Activity Relationship><Surface><T cell response><T-Cell Activation><T-Cells><T-Lymphocyte><Techniques><Technology><Therapeutic><Time><Tissues><Toxic effect><Toxicities><Tumor Antigens><Tumor Vaccines><Tumor-Associated Antigen><Vaccination><Vaccines><Veiled Cells><Work><anti-cancer therapy><anticancer therapy><antigen-specific T cells><barcode><base><cancer antigens><cancer cell><cancer in the colon><cancer therapy><cancer vaccination><chemical structure function><colon cancer progression><deep sequencing><density><design><designing><genome mutation><genome sequencing><high throughput screening><host response><immune system tolerance><immune unresponsiveness><immunogen><immunological paralysis><immunoresponse><improved><in vivo><individual patient><individualized cancer therapy><innovate><innovation><innovative><interest><intradermal injection><killer T cell><lipid nanoparticle><lymph gland><lymph nodes><lymphnodes><mRNA><mRNA delivery><mRNA vaccine><malignancy><mouse model><murine model><nano particle delivery><nano tech><nano technology><nano-technological><nanoparticle delivered><nanoparticle delivery><nanotech><nanotechnological><necrocytosis><neo-antigen><neo-antigen targeted vaccination><neo-antigen vaccination><neo-antigen vaccine><neo-epitopes><neoantigen targeted vaccination><neoantigen vaccination><neoantigen vaccine><neoantigens><neoepitopes><neoplasm/cancer><peptide aminoacid sequence><peptide sequence><personalized cancer therapy><personalized cancer treatment><physical property><post-doc><post-doctoral><protein aminoacid sequence><response><structure function relationship><success><thymus derived lymphocyte><tool><training opportunity><tumor vaccination><tumor-specific antigen><uptake><vaccine delivery><vaccine efficacy><vaccine for cancer><vaccine safety>