Tumor-Associated Antigen Delivery using Protein Nanoparticles for Combined Immunotherapy

使用蛋白质纳米颗粒进行肿瘤相关抗原递送以进行联合免疫治疗

• 批准号: 10319541
• 负责人: Szu-Wen Wang
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319541
• 关键词: Address; Adjuvant; Animals; Antigens; Antitumor Response; Applications Grants; Biodistribution; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; CT26; Cancer Model; Cancer Vaccines; Cells; Clinical; Colon Carcinoma; Combined Modality Therapy; Data; Dendritic Cells; Disease remission; Education; Epitopes; Formulation; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Memory; Immunosuppression; Immunotherapy; Impairment; In Vitro; Inbred BALB C Mice; Malignant Neoplasms; Mediating; Modeling; Mus; Outcome; Ovalbumin; Patients; Property; Proteins; Research; System; T-Cell Activation; T-Cell Depletion; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Translating; Treatment Efficacy; Tumor Antigens; Vaccines; Virion; Virus; Work; anti-CTLA4; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; base; cancer cell; cancer therapy; cancer type; checkpoint inhibition; design; gp100 Antigen; immune checkpoint; improved; improved outcome; in vivo; in vivo Model; in vivo evaluation; monocyte; nanoparticle; nanoparticle delivery; neoplasm immunotherapy; neoplastic cell; novel therapeutic intervention; response; success; targeted delivery; therapeutically effective; treatment strategy; tumor; vaccine efficacy; vaccine formulation

PROJECT SUMMARY / ABSTRACT Enthusiasm for anti-tumor immunotherapy has increased dramatically with the clinical success of immune checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4) across diverse tumor types. Checkpoint inhibitors release normal immune homeostatic mechanisms that impair the anti-tumor immune response. Despite the promise of this approach, the majority of patients do not achieve long- term remission and many cancer types do not respond to this type of therapy, felt to be due in part to inadequate education of the immune system to the relevant tumor-associated antigens. Priming the immune system during checkpoint inhibition therapy to better recognize tumor-associated antigens (TAAs), using cancer vaccines, is an attractive option for improving outcomes. A major challenge for conventional cancer vaccines, however, is their potency. To address this, TAAs have been delivered using a protein nanoparticle platform, E2, and this strategy has been shown to elicit antigen-specific destruction of cancer cells and to significantly extend survival time for tumor-bearing mice. The overall hypothesis of this proposed work is that by combining the synergistic mechanisms of increasing antigen-specific effects using the E2 nanoparticle, while simultaneously releasing the brakes on immune checkpoints, a better outcome will be achieved which prolongs survival time and sustains anti-tumor immune responses. To test this hypothesis, we propose the following specific aims: (1) Elucidate nanoparticle design and delivery strategies that will increase anti-tumor responses, and determine the mechanisms of elicited anti-tumor activity; (2) Examine the scope of E2-based vaccine efficacy by confirming activity in another tumor model in vivo and evaluating human immune responses ex vivo; and (3) Evaluate the therapeutic combination of E2- based vaccine formulations with a prototypical checkpoint inhibitor, anti-PD1, for enhanced anti-tumor immune response. This work will evaluate whether more effective immunotherapy can be achieved by increasing tumor antigen-specific responses (via E2 nanoparticle vaccines) while simultaneously blocking the checkpoints to remove immune suppression (via immune checkpoint inhibition). These studies will generate general principles for improving cancer treatment using such combination therapies. Ultimately, it can potentially provide a more effective therapeutic strategy applicable for cancer states that are conventionally difficult to treat.

项目总结/摘要 随着临床成功，抗肿瘤免疫治疗的热情急剧增加 免疫检查点抑制剂（例如，抗PD-1、抗CTLA-4）。 检查点抑制剂释放正常的免疫稳态机制，损害抗肿瘤作用。 免疫反应尽管这种方法有希望，但大多数患者并没有实现长期- 长期缓解和许多癌症类型不响应这种类型的治疗，认为部分是由于 免疫系统对相关肿瘤相关抗原的教育不足。灌注 检查点抑制治疗期间的免疫系统更好地识别肿瘤相关抗原 使用癌症疫苗的TAAs是改善结果的一个有吸引力的选择。 然而，传统癌症疫苗的一个主要挑战是它们的效力。解决 这一点，TAAs已经使用蛋白质纳米颗粒平台E2进行了递送，并且这种策略已经被 显示引发癌细胞的抗原特异性破坏，并显著延长 荷瘤小鼠。这项拟议工作的总体假设是，通过结合协同作用， 使用E2纳米颗粒增加抗原特异性作用的机制，同时 释放免疫检查点的刹车，将实现更好的结果， 存活时间并维持抗肿瘤免疫应答。为了验证这一假设，我们提出了 以下具体目标：（1）阐明纳米颗粒设计和递送策略， 抗肿瘤反应，并确定引发的抗肿瘤活性的机制;（2）检查 通过在另一种体内肿瘤模型中确认活性，确定基于E2的疫苗有效性范围， 离体评价人免疫应答;和（3）评价E2- 具有原型检查点抑制剂抗PD 1的基于疫苗的制剂，用于增强抗肿瘤 免疫反应 这项工作将评估是否可以实现更有效的免疫治疗，通过增加 肿瘤抗原特异性反应（通过E2纳米颗粒疫苗），同时阻断肿瘤抗原特异性反应。 检查点，以消除免疫抑制（通过免疫检查点抑制）。这些研究将 产生使用这种组合疗法改善癌症治疗的一般原则。 最终，它可以潜在地提供适用于癌症状态的更有效的治疗策略 这些疾病通常很难治疗。

项目成果

Engineering Protein Nanoparticles Functionalized with an Immunodominant Coxiella burnetii Antigen to Generate a Q Fever Vaccine.

• DOI: 10.1021/acs.bioconjchem.3c00317
• 发表时间: 2023-09-20
• 期刊: BIOCONJUGATE CHEMISTRY
• 影响因子: 4.7
• 作者: Ramirez, Aaron;Felgner, Jiin;Jain, Aarti;Jan, Sharon;Albin, Tyler J.;Badten, Alexander J.;Gregory, Anthony E.;Nakajima, Rie;Jasinskas, Algimantas;Felgner, Philip L.;Burkhardt, Amanda M.;Davies, D. Huw;Wang, Szu-Wen
• 通讯作者: Wang, Szu-Wen

Protein Nanoparticle-Mediated Delivery of Recombinant Influenza Hemagglutinin Enhances Immunogenicity and Breadth of the Antibody Response.

• DOI: 10.1021/acsinfecdis.2c00362
• 发表时间: 2023-02-10
• 期刊: ACS INFECTIOUS DISEASES
• 影响因子: 5.3
• 作者: Badten, Alexander J.;Ramirez, Aaron;Hernandez-Davies, Jenny E.;Albin, Tyler J.;Jain, Aarti;Nakajima, Rie;Felgner, Jiin;Davies, D. Huw;Wang, Szu-Wen
• 通讯作者: Wang, Szu-Wen