Next Generation Gene-Gun Delivered DNA and RNA Immunotherapeutic Vaccines for Melanoma.

下一代基因枪提供针对黑色素瘤的 DNA 和 RNA 免疫治疗疫苗。

• 批准号: 10760452
• 负责人: Hannah Frizzell
• 金额: $ 20万
• 依托单位: ORLANCE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10760452
• 关键词: Address; Adjuvant; Antibodies; Antigens; Antitumor Response; Blood; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cells; Clinical; Clinical Trials; Cryopreservation; DNA; DNA Maintenance; DNA Vaccines; DNA delivery; Delivery Rooms; Development; Devices; Disadvantaged; Dose; Dryness; Effectiveness; Electroporation; Epidermis; Formulation; Freeze Drying; Future; Genetic; Goals; Gold; Human; Immune Targeting; Immune response; Immunization; Immunotherapeutic agent; Immunotherapy; Intramuscular; Intramuscular Injections; Jet Injections; Lead; Malignant Neoplasms; Mediating; Melanoma Vaccine; Methods; Modality; Modeling; Mucous Membrane; Mus; Muscle; Natural Killer Cells; Needles; Nucleic Acid Vaccines; Nucleic Acids; Pain; Painless; Phase; RNA; RNA delivery; RNA vaccine; Regimen; Research; Site; Skin; Small Business Innovation Research Grant; T cell response; Technology; Temperature; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Tumor-Infiltrating Lymphocytes; Vaccination; Vaccines; Work; cancer immunotherapy; cancer therapy; clinical development; comparative efficacy; efficacy evaluation; gene gun; gp100 Antigen; immunogenicity; improved; individual patient; lipid nanoparticle; melanoma; mouse model; nanoparticle delivery; neoantigen vaccine; neoantigens; neoplastic cell; next generation; novel; nucleic acid delivery; particle; preclinical development; protective efficacy; prototype; response; therapeutic evaluation; trafficking; tumor; vaccine delivery

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.

项目摘要 Orlance开发了下一代基因枪（MACH-1 GG），可有效地将DNA和RNA传递到 表皮细胞，导致鲁棒的免疫反应。 鉴定针对癌症疫苗的个性化新抗原。 可以有效递送的技术传递癌症，并促进局部肿瘤的指示 仍然需要特定的T细胞响应。 实现细胞内交付的配方或交付技术提供了可观的希望 这些目标包括电动穿孔（EP）或IM递送DNA或脂质纳米的喷射（LNP） 对于IM的递送，这些交付方式有不同的缺点 对于高剂量（1-5毫克DNA），由于稳定​​性有限（RNA/LNP），反应生成或疼痛而导致的超冷储存 在管理后，对特定组织的海拔免疫反应的能力有限。 室温稳定的冻干DNA或金微粒上的RNA疫苗。 并直接将细胞内递送到皮肤细胞中，低剂量（1-4 µg）导致全身性，粘膜和 局部皮肤免疫反应可以为癌症的信任提供好处 黑色素瘤。 I期临床试验中的反应。 设备。 并检验以下假设，即MACH-1将在其他其他DNA/RNA中提供免疫原性和疗效的优势 黑色素瘤的递送技术。 增加了MACH-1 DNA和RNA疫苗诱导黑色素瘤特异性T细胞反应的能力。 将确定将DNA和RNA在相同剂量中还是在促进方案中相结合会产生协同作用。 我们将比较通过EP或RNA的MACH-1传递DNA和/或RNA黑色素瘤疫苗与DNA的递送 LNP的免疫原性和小鼠的保护效果。 目标1：研究遗传佐剂对GG递送DNA的免疫原性和功效的影响 RNA黑色素瘤疫苗2：确定是否合并了优化的佐剂DNA和RNA疫苗 与EP递送相比 黑色素瘤小鼠模型中RNA的DNA和LNP递送。 建立MACH-1作为输送癌症疫苗的有效装置。