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: 10402178
• 负责人: CHAD A. MIRKIN
• 金额: $ 52.19万
• 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/10402178
• 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; Ensure; Epitopes; Evaluation; Foundations; Future; Goals; Health; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunization; Immunocompetent; 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; 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; base; cancer therapy; chemical synthesis; clinical translation; clinically relevant; cytotoxic CD8 T cells; design; efficacy evaluation; humanized mouse; immune activation; immune checkpoint blockade; 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; vaccination outcome

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.

项目概要/摘要 这项研究将利用球形核酸（SNA）纳米结构来开发有效的、结构知情的 晚期黑色素瘤的传统治疗（即化疗或放疗）不太成功。 由于难以辨别黑色素瘤细胞的表型，因此必须确保黑色素瘤的免疫治疗。 具有高突变负担的黑色素瘤无法轻易逃避免疫系统的作用。 作为强大的癌症疫苗，通过精确控制多种黑色素瘤相关的表现 SNA 由纳米颗粒组成，针对免疫细胞，降低其免疫逃避的可能性。 使用免疫刺激“佐剂”合成时具有致密放射状核酸壳的核心。 事实上，这种仅佐剂的结构证明了寡核苷酸、SNA 诱导免疫反应。 与线性佐剂相比，3D 结构产生的反应增强，并构成了 正在进行的 1b/2 期临床试验我们利用了化学合成的简便性和模块化架构。 SNA，并将其合成为包含佐剂和单一肿瘤相关肽（“抗原”）。 结构增强抗肿瘤反应并在模型系统中提供长期的保护性免疫力 特别是，在我们提出的工作中，我们的目标是疫苗结构和功效之间存在密切关系。 通过精确整合和呈现多种成分来开发针对黑色素瘤的 SNA 疫苗 免疫系统的免疫刺激信号将与多种临床相关的物质一起合成。 黑色素瘤抗原（MHC-I 和 -II 限制性、肿瘤相关性、新抗原），其结构存在差异 结合体外和体内评估，提出了佐剂和抗原的结构控制。 免疫刺激，将阐明结构-活性关系，为癌症疫苗的未来提供信息 使用结构来控制多种免疫系统线索的呈现具有提升的能力。 在目标 1 中，我们将合成含有黑色素瘤的免疫反应并改善临床结果。 多种抗原和不同的稳定性可增强抗原特异性 T 细胞反应。 免疫细胞、SNA 成分的亚细胞运输以及多种途径激活的动力学 （例如抗原呈递、共刺激标记物表达）在目标 2 中，我们将比较不同的给药方式。 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 我们将评估含有 SNA 的免疫活性小鼠体内产生的反应。 在目标 3 中，我们将评估 SNA 的抗肿瘤功效。 单独体内以及与免疫检查点阻断相结合，并确定 SNA 作为进一步的候选者 值得注意的是，这种方法将产生基于结构的方法。 了解 SNA 作为疫苗的性能，并通过产生广泛的 T 细胞来改善免疫治疗 反应具有优越的功效。