Investigating TLR-agonist adjuvancy in STING-activating nanoparticle cancer vaccines

研究 STING 激活纳米颗粒癌症疫苗中的 TLR 激动剂佐剂

• 批准号: 10331814
• 负责人: Zachary Bennett
• 金额: $ 3.79万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331814
• 关键词: Adaptor Signaling Protein; Address; Adjuvant; Agonist; Antigen Presentation; Antigen-Presenting Cells; Antigens; Binding; Biological Assay; CD86 gene; CXCL10 gene; Cancer Vaccines; Cells; Clinical; Cyclic GMP; Cytotoxic T-Lymphocytes; DNA; Dendritic Cells; Dose; Encapsulated; Endosomes; Enzyme-Linked Immunosorbent Assay; Failure; Flow Cytometry; Formulation; Gene Activation; Generations; Genes; Genetic Transcription; IRF3 gene; Imiquimod; Immune; Immunologic Receptors; In Vitro; Individual; Inflammatory; Interferon Type I; Interferon Type II; Interferons; Interleukin-1 beta; Interleukin-6; Kinetics; Laboratories; Lead; Ligands; Lymphocyte; Malignant Neoplasms; Measures; Mediating; Micelles; Modeling; Mus; Natural Immunity; Nucleic Acids; Pathway interactions; Patients; Pattern Recognition; Pattern recognition receptor; Phagocytes; Phagocytosis; Phase III Clinical Trials; Polymers; Process; Production; Property; Receptor Activation; Refractory; Reporter; Signal Pathway; Signal Transduction; Specificity; Splenocyte; Stimulator of Interferon Genes; Stimulus; T cell response; T memory cell; TBK1 gene; TLR7 gene; TNF gene; Therapeutic; Toll-like receptors; Tumor Antigens; Tumor Burden; Tumor Immunity; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Therapy; Vaccines; amphiphilicity; anti-tumor immune response; cancer testis antigen; cancer vaccination; cell type; copolymer; cytokine; draining lymph node; effective therapy; immune checkpoint blockade; immunoregulation; immunosuppressed; improved; in vivo; innate immune pathways; innovation; lymph nodes; lymphocyte proliferation; macrophage; melanoma; nanoparticle; novel; receptor; refractory cancer; response; self assembly; sensor; small molecule; spatiotemporal; synergism; treatment response; tumor; tumor growth; vaccine efficacy

Project Summary/Abstract Therapeutic vaccination against melanoma has yet to realize its clinical potential. Several phase III clinical trials assessing efficacy of vaccination against cancer-testis antigens, whole cell lysates, or cancer associated antigens failed to meet their therapeutic endpoints. This failure is due to lack of antigen-specific cytotoxic T lymphocyte proliferation after vaccination. It is known vaccine efficacy requires spatiotemporal draining of both antigen and adjuvant to lymph nodes for stimulating innate immunity as well as antigen presentation. Because of their size and physicochemical properties, nanoparticle vaccines enable precision delivery of both antigen and adjuvant to relevant cell types in the lymph node. However, sufficient amplification of intracellular danger signals can remain challenging. Recently, our laboratory has discovered an amphiphilic block copolymer, PEG-b-PC7A, which directly binds and activates the stimulator of interferon genes (STING). This innate immune receptor generally recognizes cytosolic DNA, processed by cyclic GMP-AMP Synthase (cGAS) to its natural ligand 2’3’- cyclic GMP-AMP (cGAMP). However, PEG-b-PC7A directly binds to STING in a cGAS-cGAMP-independent process, amplifying the secretion of type I interferons after phagocytosis by antigen presenting cells. We have shown vaccinating tumor-bearing mice with a PC7A polymeric micelle and tumor-associated antigen formulation will lead to tumor growth inhibition. While this polymer shows remarkable nanoparticle self-assembly, pH- responsiveness, endosomolytic, and STING activating properties, anti-tumor immune response can be refractory in immunosuppressive tumor models. Therefore, I will address this problem by incorporating additional immuno- modulatory components in our formulation. Particularly, low expression of inflammatory cytokines will be addressed. I will formulate PC7A nanoparticle with toll-like receptor (TLR) agonists to increase expression of cytokines in non-redundant manners. While the TLR and STING pathways both converge on expression of type I interferons, the differences in adaptor proteins and signaling pathways (e.g. NF-κB) can lead to significant changes in the kinetics of cytokines expression after vaccination by unique agonists. In this application I will screen and identify PC7A nanoparticles encapsulating TLR agonists for improved interferon stimulation, CTL generation, and anti-tumor immunity. I hypothesize the TLR-7 agonist, Imiquimod (R837), encapsulated PC7A nanoparticles will show improved anti-tumor immunity due to non-redundancy in TLR7/STING-IRF3/7-induced transcription of type I interferons. This application will show innovation by formulating a new class of synergetic TLR-STING agonist nanoparticles, and the proposal is suited for this project because of the remarkable properties of the PC7A polymeric nanoparticles.

项目摘要/摘要 针对黑色素瘤的治疗疫苗尚未实现其临床潜力。几个III期临床试验 评估癌症抗原，全细胞裂解物或相关癌症的疫苗接种效率 抗原未能达到其治疗终点。这种失败是由于缺乏抗原特异性细胞毒性T 疫苗后淋巴细胞增殖。已知疫苗效率需要两者的时空排水 抗原并调整为淋巴结，以刺激先天免疫以及抗原表现。因为 纳米颗粒疫苗的大小和物理特性，可以精确递送抗原和 淋巴结中相关细胞类型的佐剂。但是，细胞内危险信号足够的扩增 可能仍然受到挑战。最近，我们的实验室发现了两亲块共聚物PEG-B-PC7A， 它直接结合并激活干扰素基因的刺激剂（STING）。这个先天免疫接收器 通常识别通过环状GMP-AMP合酶（CGA）处理的胞质DNA，其天然配体2'3'-- 环状GMP-AMP（CGAMP）。但是，PEG-B-PC7A直接与CGAS-CGAMP无关的刺激 过程，扩大了抗原呈递细胞吞噬作用后I型干扰素的分泌。我们有 用PC7A聚合物胶束和与肿瘤相关的抗原配方显示了疫苗接种肿瘤的小鼠 将导致肿瘤生长抑制。尽管该聚合物显示出显着的纳米颗粒自组装，但 反应性，内溶性和刺激激活特性，抗肿瘤免疫增强响应可能是难治性的 在免疫抑制肿瘤模型中。因此，我将通过编码其他免疫 - 我们公式中的调节组件。特别是，炎性细胞因子的低表达将是 解决。我将用Toll样受体（TLR）激动剂制定PC7A纳米颗粒，以增加表达 细胞因子以非冗余的方式。而TLR和STING途径都融合了类型的表达 我干涉，衔接蛋白和信号通路（例如NF-κB）的差异可能导致显着 独特激动剂疫苗接种后细胞因子表达的动力学的变化。在此应用程序中，我将 屏幕并识别封装TLR激动剂的PC7A纳米颗粒，以改善干扰刺激，CTL 产生和抗肿瘤免疫学。我假设TLR-7激动剂咪喹莫德（R837）封装PC7A 由于TLR7/Sting-irf3/7诱导的非差异，纳米颗粒将显示出改善的抗肿瘤免疫学 I型干扰素的转录。该应用程序将通过制定新的协同效果来显示创新 TLR刺激性激动剂纳米颗粒，该提案适合该项目，因为很棒 PC7A聚合物纳米颗粒的性质。