Innovative Research for Cancer Nanotechnology (IRCN) for Enhancing Melanoma-specific Immune Responses by the Rational Design of Spherical Nucleic Acids

通过合理设计球形核酸增强黑色素瘤特异性免疫反应的癌症纳米技术 (IRCN) 创新研究

• 批准号: 10591545
• 负责人: CHAD A. MIRKIN
• 金额: $ 50.89万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-14 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591545
• 关键词: Adjuvant; Agonist; Animals; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Antitumor Response; Architecture; Biodistribution; Biological Models; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Vaccines; Cells; Chemicals; Chemotherapy and/or radiation; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Clinical Treatment; Cues; Development; Disease; Enhancement Technology; Ensure; Epitopes; Evaluation; Foundations; Future; Goals; Health; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunocompetent; Immunologic Stimulation; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Innate Immune Response; Intravenous; Kinetics; Malignant Neoplasms; Melanoma Cell; Melanoma Vaccine; Modeling; Modification; Monophenol Monooxygenase; Mus; Mutation; Nanostructures; Nanotechnology; Nucleic Acid Vaccines; Nucleic Acids; Nucleosome Core Particle; Oligonucleotides; Outcome; Pathway interactions; Patients; Peptides; Performance; Phase Ib/II Clinical Trial; Phase Ib/II Trial; Phenotype; Positioning Attribute; Proteins; Radial; Radiation; Research; Route; SILV gene; Signal Pathway; Specimen; Spherical Nucleic Acids; Structure; Structure-Activity Relationship; T cell response; TLR9 gene; Technology; Testing; Therapeutic; Translations; Tumor Burden; Tumor Escape; Vaccination; Vaccine Design; Vaccines; Variant; Work; anti-tumor immune response; anticancer research; antigen-specific T cells; cancer therapy; chemical synthesis; clinical translation; clinically relevant; cytotoxic CD8 T cells; design; efficacy evaluation; humanized mouse; immune activation; immune checkpoint blockade; immune stimulatory agent; improved; in vitro testing; in vivo; in vivo Model; in vivo evaluation; innovation; melanoma; melanoma-associated antigen; mouse model; nanoparticle; nanoscale; nanotherapeutic; neoantigens; nucleic acid structure; patient subsets; preclinical study; prevent; programmed cell death ligand 1; programmed cell death protein 1; rational design; receptor; research clinical testing; response; stoichiometry; subcutaneous; success; three dimensional structure; trafficking; tumor; tumor microenvironment; uptake; Adjuvant; Agonist; Animals; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Antitumor Response; Architecture; Biodistribution; Biological Models; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Vaccines; Cells; Chemicals; Chemotherapy and/or radiation; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Clinical Treatment; Cues; Development; Disease; Enhancement Technology; Ensure; Epitopes; Evaluation; Foundations; Future; Goals; Health; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunocompetent; Immunologic Stimulation; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Innate Immune Response; Intravenous; Kinetics; Malignant Neoplasms; Melanoma Cell; Melanoma Vaccine; Modeling; Modification; Monophenol Monooxygenase; Mus; Mutation; Nanostructures; Nanotechnology; Nucleic Acid Vaccines; Nucleic Acids; Nucleosome Core Particle; Oligonucleotides; Outcome; Pathway interactions; Patients; Peptides; Performance; Phase Ib/II Clinical Trial; Phase Ib/II Trial; Phenotype; Positioning Attribute; Proteins; Radial; Radiation; Research; Route; SILV gene; Signal Pathway; Specimen; Spherical Nucleic Acids; Structure; Structure-Activity Relationship; T cell response; TLR9 gene; Technology; Testing; Therapeutic; Translations; Tumor Burden; Tumor Escape; Vaccination; Vaccine Design; Vaccines; Variant; Work; anti-tumor immune response; anticancer research; antigen-specific T cells; cancer therapy; chemical synthesis; clinical translation; clinically relevant; cytotoxic CD8 T cells; design; efficacy evaluation; humanized mouse; immune activation; immune checkpoint blockade; immune stimulatory agent; improved; in vitro testing; in vivo; in vivo Model; in vivo evaluation; innovation; melanoma; melanoma-associated antigen; mouse model; nanoparticle; nanoscale; nanotherapeutic; neoantigens; nucleic acid structure; patient subsets; preclinical study; prevent; programmed cell death ligand 1; programmed cell death protein 1; rational design; receptor; research clinical testing; response; stoichiometry; subcutaneous; success; three dimensional structure; trafficking; tumor; tumor microenvironment; uptake

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.

项目摘要/摘要 这项研究将利用球形核酸（SNA）纳米结构来发展有效的结构信息 晚期黑色素瘤的疫苗。传统治疗（即化学疗法或放射线）的成功率较低 黑色素瘤由于难以辨别黑色素瘤细胞表型。免疫治疗剂必须确保 这种黑色素瘤（具有高突变烧伤）很容易逃避免疫系统。 SNA可以起作用 作为良好的癌症疫苗通过对多种黑色素瘤相关的表现的精确控制 靶向免疫细胞的靶标，可降低其免疫进化的潜力。 SNA由纳米颗粒组成 核心核酸的密集径向壳。使用免疫刺激性“佐剂”合成时 寡核苷酸，SNA诱导免疫复杂。确实，这种调整结构证明了 与线性调整相比，3D结构产生的响应增强并构成了 正在进行的1B/2期临床试验。我们探索了化学合成和模块化结构的易 SNA，并合成它们，包括调整和单个肿瘤相关的肽（“抗原”）。这些 结构增强抗肿瘤反应，并在模型系统中提供长期保护的免疫力，并在 特别是，疫苗结构与效率之间存在牢固的关系。在我们提出的工作中，我们的目标 通过精确融合和呈现多重来开发针对黑色素瘤的SNA疫苗 免疫刺激性提示。 SNA将与多个临床相关的合成 黑色素瘤抗原（MHC-I和-II受限制，肿瘤相关的新抗原），其结构变化 提出了调节和抗原。控制结构，结合体外和体内评估 免疫刺激将阐明结构活性关系，这将为癌症疫苗的未来提供信息 设计。使用结构来控制多个免疫系统提示的呈现，具有提升的力量 对黑色素瘤的免疫反应并改善临床结局。在AIM 1中，我们将合成包含SNA的 多种抗原和不同的稳定性，以增强抗原特异性T细胞反应。我们将分析他们的吸收 通过免疫细胞，SNA成分的亚细胞运输以及多个途径激活的动力学 （例如，抗原表现，共刺激标记表达）。在AIM 2中，我们将比较不同的管理 路线和分析体内生物分布和摄取动力学以及抗原特异性免疫反应 在免疫能力小鼠中由SNA饲养。我们将在交付含有SNA的含量后评估提出的响应 人源化小鼠和患者标本的人类抗原。在AIM 3中，我们将评估SNA抗肿瘤效率 单独的体内并与免疫障碍物结合在一起，并将SNA识别为进一步的候选者 临床前研究和临床翻译。值得注意的是，这种方法将产生基于结构的 了解SNA性能作为疫苗，并通过产生T细胞广度来改善免疫疗法 效率较高的响应。