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Principal Investigator: Hannah Frizzell
Organization: ORLANCE, INC.
Fiscal Year: 2024
Award: $200,000
Funding agency: National Cancer Institute
PROJECT SUMMARY
Orlance has developed a next-generation Gene Gun (MACH-1 GG) that efficiently delivers DNA and RNA into
epidermal cells, leading to robust immune responses. Sequencing of tumors from individual patients has led to
the identification of personalized neoantigens that could be targeted with cancer vaccines. However,
technologies that can effectively deliver these cancer neoantigens and promote the induction of localized tumor
specific T cell responses are still needed. Nucleic acid (NA; DNA and RNA) vaccines administered using specific
formulations or delivery technologies that achieve intracellular delivery offer considerable promise to achieve
this goal. These include electroporation (EP) or jet injection for IM delivery of DNA or lipid nanoparticles (LNPs)
for IM delivery of RNA. These delivery modalities, however, have different drawbacks including a requirement
for high doses (1-5 mg of DNA), ultra-cold storage due to limited stability (RNA/LNPs), reactogenicity or pain
post-administration, and a limited ability to target immune responses to specific tissues. The GG entails the
delivery of room temperature stable lyophilized DNA or RNA vaccines on gold microparticles. It achieves painless
and direct intracellular delivery into skin cells with very low doses (1-4 µg) that results in systemic, mucosal and
localized skin immune responses that could provide a benefit for treatment of cancers and, in particular,
melanoma. The MACH-1 GG is based on a previous successful GG that induced strong antibody and T cell
responses in phase I human clinical trials. The MACH-1 provides significant improvements over this earlier
device. Here, we will investigate the feasibility of using MACH-1 to deliver DNA or RNA cancer vaccines in mice
and test the hypothesis that MACH-1 will offer advantages in immunogenicity and efficacy over other DNA/RNA
delivery technologies for melanoma. We will first determine if co-delivering a novel set of genetic adjuvants will
increase the ability of MACH-1 DNA and RNA vaccines to induce melanoma-specific T cell responses. Next, we
will determine if combining DNA and RNA in the same dose or in a prime-boost regimen offers synergistic effects.
We will then compare MACH-1 delivery of DNA and/or RNA melanoma vaccines to DNA delivery by EP or RNA
delivery by LNPs for immunogenicity and protective efficacy in mice. This work will be accomplished in two Aims:
Aim 1: Investigate the impact of genetic adjuvants on the immunogenicity and efficacy of GG delivered DNA and
RNA melanoma vaccines. Aim 2: Determine if combining the optimized adjuvanted DNA and RNA vaccines in
the same dose or in a prime-boost regimen enhances immunogenicity and efficacy compared to EP delivery of
DNA and LNP delivery of RNA in a mouse model of melanoma. Successful completion of these Aims will
establish MACH-1 as an effective device to deliver cancer vaccines.
Terms: <Address><Adjuvant><Antibodies><Antigens><Antineoplastic Vaccine><Antitumor Response><Biolistics><Blood><Blood Reticuloendothelial System><Body Tissues><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Treatment><Cancer Vaccines><Cancers><Cell Body><Cells><Clinical><Clinical Trials><Cryofixation><Cryopreservation><Cytotoxic cell><DNA><DNA Maintenance><DNA Stability><DNA Vaccines><DNA delivery><Delivery Rooms><Deoxyribonucleic Acid><Development><Devices><Disadvantaged><Dose><Dryness><Effectiveness><Electroporation><Epidermis><Formulation><Freeze Drying><Freeze Dryings><Future><Gene-Gun Technique><Genetic><Goals><Gold><Hospital Birth Centers><Hospital Birthing Centers><Human><Immune Targeting><Immune mediated therapy><Immune response><Immunization><Immunological response><Immunologically Directed Therapy><Immunotherapeutic agent><Immunotherapy><Intramuscular><Intramuscular Injections><Jet Injections><K lymphocyte><Lead><Lyophilization><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Melanoma><Melanoma Tumor><Melanoma Vaccine><Methods><Mice><Mice Mammals><Modality><Modeling><Modern Man><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Muscle><Muscle Tissue><NK Cells><Naked DNA Vaccines><Natural Killer Cells><Needles><Neoplasm Vaccines><Non-Polyadenylated RNA><Nucleic Acid Vaccines><Nucleic Acids><Pain><Painful><Painless><Pb element><Phase><RNA><RNA Gene Products><RNA delivery><RNA vaccine><RNA-based vaccine><Recombinant DNA Vaccines><Regimen><Research><Ribonucleic Acid><SBIR><Site><Skin><Small Business Innovation Research><Small Business Innovation Research Grant><T cell response><T8 Cells><T8 Lymphocytes><Technology><Temperature><Testing><Therapeutic><Time><Tissues><Treatment Efficacy><Tumor Cell><Tumor Vaccines><Tumor growth in melanoma><Tumor-Infiltrating Lymphocytes><Vaccination><Vaccines><Work><anti-cancer immunotherapy><anti-cancer therapy><anti-tumor response><anti-tumor vaccine><anticancer immunotherapy><booster dose><booster shot><booster vaccine><cancer immunotherapy><cancer therapy><cancer-directed therapy><clinical development><cold preservation><cold storage><comparable efficacy><comparative efficacy><compare efficacy><deliver DNA><deliver vaccines><determine efficacy><developmental><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><electroporative delivery><evaluate efficacy><examine efficacy><gene electrotransfer><gene gun><glycoprotein 100><gp 100><gp100 Antigen><heavy metal Pb><heavy metal lead><host response><immune drugs><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><immuno therapy><immunogen><immunogenicity><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><improved><individual patient><intervention efficacy><intramuscular drug administration><lipid based nanoparticle><lipid nanoparticle><mRNA vaccine><mRNA-based vaccine><malignancy><mouse model><murine model><muscular><nano particle delivery><nanoparticle delivered><nanoparticle delivery><neo-antigen><neo-antigen vaccine><neo-epitopes><neoantigen vaccine><neoantigens><neoepitopes><neoplasm/cancer><neoplastic cell><next generation><non-painful><nonpainful><not painful><novel><nucleic acid delivery><nucleic acid-based vaccine><particle><pre-clinical development><preclinical development><protective efficacy><prototype><response><therapeutic efficacy><therapeutic evaluation><therapeutic testing><therapy efficacy><trafficking><tumor><vaccine boost><vaccine delivery><vaccine for cancer>