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: 10312341
• 负责人: Jayanth Panyam
• 金额: $ 37.41万
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10312341
• 关键词: Address; Agonist; Antibodies; Antigens; Applications Grants; Bacillus Calmette-Guerin Therapy; Basal cell carcinoma; Biological Assay; Breast Cancer Model; Cell surface; Cell-Mediated Cytolysis; Cells; Characteristics; Charge; Chemosensitization; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Dendritic Cells; Drug Combinations; Drug Delivery Systems; Drug Kinetics; ERBB2 gene; Encapsulated; 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; 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; base; 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像受体（TLR）的激动剂是有希望的抗癌疫苗佐剂，因为它们的能力 诱导促炎性细胞因子产生强大的免疫反应。但是，目前可用 TLR激动剂受到许多局限性，包括自我调节性免疫抑制和不利 局部药代动力学导致树突状细胞内的可用性差。此外，当前基于TLR激动剂 抗癌疫苗会产生强大的细胞毒性CD8 T细胞反应，但不是CD4 TH 1辅助T细胞反应， 这对于诱导有效的长期抗肿瘤免疫至关重要。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。我们的团队已经开发了一个套件 激活TLR7和/8的高度取代的Imidazoquinolines，并诱导更高水平 与FDA批准的TLR7激动剂相比，细胞因子与咪喹莫德相比。我们的研究表明促炎之间的平衡 可以通过结构修饰调节免疫抑制性细胞因子。封装 这些新型激动剂在酸性pH反应式纳米颗粒（NP）中导致CD4和COB的强化激活 T细胞和天然杀手（NK）细胞，导致比自由激动剂更强的抗癌免疫反应 或封装在非PH响应NP中。重要的是，使用空心的NP疫苗的皮内输送 微针平台导致了增强的Th1免疫反应，这对于有效诱导至关重要 长期抗肿瘤免疫。我们将基于这些令人兴奋的发现，并进一步优化新的激动剂 有效封装在pH响应的NP中，调整NP性能以改善树突状细胞的靶向 通过空心微针输送后，研究了NK细胞介导的抗体介导的增强 细胞细胞毒性。该修订后的R01赠款申请的具体目的包括： AIM 1：设计和合成针对NP封装优化的TLR7/8激动剂 AIM 2：优化空心微对辅助ID输送的pH响应式NP公式 AIM 3：确定空心微针ID输送后NP疫苗的抗癌疗效 我们希望我们的研究将确定克服TLR激动剂的新设计原理和交付策略 当前抗癌疫苗的局限性并进一步推进了癌症免疫疗法的领域。