Tumor-Associated Antigen Delivery using Protein Nanoparticles for Combined Immunotherapy

项目摘要/摘要 随着临床的成功，人们对抗肿瘤免疫治疗的热情急剧上升。 免疫检查点抑制剂(例如，抗PD-1、抗CTLA-4)在不同类型的肿瘤中的应用。 检查点抑制因子释放破坏抗肿瘤作用的正常免疫平衡机制 免疫反应。尽管这种方法前景看好，但大多数患者并没有实现长期的- 足月缓解和许多癌症类型对这种治疗没有反应，认为部分原因是 免疫系统对相关肿瘤相关抗原的教育不足。引爆 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(TAAS)是改善结果的一个有吸引力的选择。 然而，传统癌症疫苗面临的一个主要挑战是它们的效力。致信地址 这是一种使用蛋白质纳米颗粒平台E2的TAAs，这一策略已经被 被证明可以诱导抗原特异性的癌细胞破坏，并显著延长癌症患者的生存时间 荷瘤小鼠。这项拟议工作的总体假设是，通过结合协同效应 使用E2纳米颗粒同时增强抗原特异性作用的机制 放开免疫检查站的刹车，将会取得更好的结果，延长 延长生存时间，维持抗肿瘤免疫反应。为了检验这一假设，我们提出了 以下具体目标：(1)阐明纳米颗粒的设计和交付战略，将增加 抗肿瘤反应，并确定诱导抗肿瘤活性的机制；(2)检测 通过确认在另一个肿瘤模型中的体内活性和 评估体外人体免疫反应；以及(3)评估E2-2的治疗组合。 基于含有典型检查点抑制剂抗PD1的疫苗配方，用于增强抗肿瘤 免疫反应。 这项工作将评估是否可以通过增加 肿瘤抗原特异性反应(通过E2纳米疫苗)，同时阻断 检查点以消除免疫抑制(通过免疫检查点抑制)。这些研究将 制定使用这种联合疗法改善癌症治疗的一般原则。 最终，它可能提供一种适用于癌症状态的更有效的治疗策略。 传统上难以治疗的疾病。

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.