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

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.

项目总结/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 晚期黑色素瘤疫苗。传统治疗（即化疗或放疗）对于 黑色素瘤，因为难以辨别黑色素瘤细胞的表型。免疫治疗必须确保 黑色素瘤--高突变负荷--不能轻易逃避免疫系统。SNA可以发挥作用 作为强大的癌症疫苗，通过精确控制多种黑色素瘤相关 靶向免疫细胞，从而降低其免疫逃避的可能性。SNA由纳米颗粒组成， 核内有密集的放射状核酸壳。当使用免疫刺激“佐剂”合成时， 在寡核苷酸中，SNA诱导免疫应答。事实上，这种仅佐剂的结构证明了 与线性佐剂相比，从3D结构产生的增强的应答，并形成了免疫治疗的基础。 正在进行的1b/2期临床试验。我们已经利用了化学合成的便利性和模块化结构， SNA，并合成它们以包括佐剂和单个肿瘤相关肽（“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性免疫，并且在 特别是，疫苗结构和效力之间有很强的关系。在我们提出的工作中，我们的目标是 开发针对黑色素瘤的SNA疫苗， 免疫系统的免疫刺激信号。SNA将与多个临床相关的 黑色素瘤抗原（MHC-I和-II限制性的，肿瘤相关的，新抗原），具有如何 呈递佐剂和抗原。结构控制，结合体外和体内评价 免疫刺激，将阐明结构-活性关系，将告知癌症疫苗的未来 设计使用结构来控制多种免疫系统提示的呈现， 对黑色素瘤的免疫应答和改善的临床结果。在目标1中，我们将合成含有 多种抗原和不同的稳定性以增强抗原特异性T细胞应答。我们将分析他们的摄取量 通过免疫细胞，SNA组分的亚细胞运输，以及多种途径激活的动力学 (e.g.抗原呈递、共刺激标志物表达）。在目标2中，我们将比较不同的管理 途径和分析体内生物分布和摄取动力学，以及抗原特异性免疫应答 在免疫活性小鼠中通过SNA产生。我们将在提交SNA后评估提出的答复， 人抗原用于人源化小鼠和患者样本。在目标3中，我们将评估SNA在以下患者中的抗肿瘤功效： 体内单独和与免疫检查点阻断组合，并将SNA鉴定为进一步免疫检查点阻断的候选物。 临床前研究和临床翻译。值得注意的是，这种方法将生成基于结构的 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。 具有上级功效的反应。