TLR7/8 agonist design and delivery for effective anticancer immune response

TLR7/8 激动剂设计和递送以实现有效的抗癌免疫反应

• 批准号: 10643962
• 负责人: Jayanth Panyam
• 金额: --
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-08 至 2023-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10643962
• 关键词: Activated Natural Killer Cell; Agonist; Antibodies; Antigens; Applications Grants; Bacillus Calmette-Guerin Therapy; Basal cell carcinoma; Biological Assay; Breast Cancer Model; Cancer Vaccines; Cell surface; Cells; Characteristics; Charge; Chemosensitization; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Dendritic Cells; Drug Combinations; Drug Delivery Systems; Drug Kinetics; ERBB2 gene; Encapsulated; Endosomes; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor Receptor; Equilibrium; FDA approved; Formulation; Helper-Inducer T-Lymphocyte; Human; Human Papillomavirus; Imiquimod; Immune; Immune response; Immunosuppression; Infiltration; Inflammatory; Injections; Interleukin-10; Investigation; Lead; Ligands; Lipid A; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Modeling; Modification; Myeloid-derived suppressor cells; Natural Killer Cells; Needles; Ovalbumin; Particle Size; Peripheral Blood Mononuclear Cell; Prodrugs; Property; Rattus; Regulatory T-Lymphocyte; Safety; Series; Site; Specificity; Structure; Surface; System; T cell response; T-Lymphocyte; TLR7 gene; Techniques; Toll-like receptors; Tumor Immunity; Up-Regulation; Vaccination; Vaccine Adjuvant; Vaccines; Viscosity; analog; anti-cancer; antibody-dependent cell cytotoxicity; antigen-specific T cells; cancer immunotherapy; cancer type; cytokine; cytotoxic; cytotoxic CD8 T cells; design; draining lymph node; drug discovery; immunotoxicity; improved; malignant breast neoplasm; nanoparticle; nanoparticle delivery; nanovaccine; novel; response; small molecule; systemic toxicity; trafficking; tumor

Agonists of toll like receptors (TLRs) are promising anticancer vaccine adjuvants because of their ability to induce proinflammatory cytokines necessary to generate a robust immune response. However, currently available TLR agonists suffer from a number of limitations including self-regulatory immunosuppression and unfavorable local pharmacokinetics resulting in poor availability within dendritic cells. Further, current TLR agonist-based anticancer vaccines generate a robust cytotoxic CD8 T cell response but not CD4 Th 1 helper T cell response, which is critical for inducing effective, long-term antitumor immunity. We will address these important challenges through a synergistic combination of drug discovery and drug delivery efforts. Our team has developed a suite of highly substituted imidazoquinolines, which activate TLR7 and/or 8 and induce significantly higher levels of cytokines compared to imiquimod, an FDA approved TLR7 agonist. Our studies show the balance between proinflammatory and immunosuppressive cytokines can be tuned through structural modifications. Encapsulation of these novel agonists in acidic pH responsive nanoparticles (NPs) resulted in robust activation of CD4 and COB T cells as well as natural killer (NK) cells, leading to a stronger anticancer immune response than free agonist or that encapsulated in non-pH responsive NPs. Importantly, intradermal delivery of NP vaccine using a hollow microneedle platform led to an enhanced Th1 immune response, which is essential for effective induction of long-term antitumor immunity. We will build on these exciting findings and further optimize the new agonists for efficient encapsulation in pH responsive NPs, tune the NP properties for improved targeting of dendritic cells following delivery via hollow microneedles, and investigate potentiation of NK cell-mediated antibody-mediated cellular cytotoxicity. The Specific Aims of this revised R01 grant application include: Aim 1: Design and synthesize TLR7/8 agonists that are optimized for NP encapsulation Aim 2: Optimize pH responsive NP formulation for hollow microneedle-assisted ID delivery Aim 3: Determine anticancer efficacy of NP vaccine following hollow microneedle-assisted ID delivery We expect our studies will identify new design principles and delivery strategies for TLR agonists that overcome the limitations of current anticancer vaccines and further advance the field of cancer immunotherapy.

Toll 样受体 (TLR) 激动剂是有前途的抗癌疫苗佐剂，因为它们能够 诱导产生强烈免疫反应所必需的促炎细胞因子。不过，目前可用 TLR 激动剂存在许多局限性，包括自我调节免疫抑制和不利的副作用。 局部药代动力学导致树突状细胞内的可用性较差。此外，目前基于 TLR 激动剂的 抗癌疫苗会产生强大的细胞毒性 CD8 T 细胞反应，但不会产生 CD4 Th 1 辅助 T 细胞反应， 这对于诱导有效、长期的抗肿瘤免疫力至关重要。我们将解决这些重要的挑战 通过药物发现和药物输送工作的协同组合。我们的团队开发了一套 高度取代的咪唑喹啉，可激活 TLR7 和/或 8 并诱导显着更高水平的 与 FDA 批准的 TLR7 激动剂咪喹莫特相比。我们的研究表明促炎症之间的平衡 免疫抑制细胞因子可以通过结构修饰进行调整。封装 这些酸性 pH 响应纳米颗粒 (NP) 中的新型激动剂导致 CD4 和 COB 的强烈激活 T 细胞以及自然杀伤 (NK) 细胞，比游离激动剂产生更强的抗癌免疫反应 或封装在非 pH 响应性纳米颗粒中。重要的是，使用空心注射器皮内注射 NP 疫苗 微针平台增强了 Th1 免疫反应，这对于有效诱导 长期抗肿瘤免疫力。我们将在这些令人兴奋的发现的基础上进一步优化新的激动剂 有效封装于 pH 响应型 NP 中，调整 NP 特性以改善树突状细胞的靶向性 通过空心微针递送后，并研究 NK 细胞介导的抗体介导的增强作用 细胞的细胞毒性。修订后的 R01 拨款申请的具体目标包括： 目标 1：设计和合成针对 NP 封装进行优化的 TLR7/8 激动剂 目标 2：优化 pH 响应型 NP 配方，用于空心微针辅助 ID 递送 目标 3：确定空心微针辅助 ID 递送后 NP 疫苗的抗癌功效 我们期望我们的研究能够确定 TLR 激动剂的新设计原则和递送策略，以克服 现有抗癌疫苗的局限性并进一步推进癌症免疫治疗领域。