STING-Activating Polymeric Nanovaccines for T Cell Therapy of Melanoma

摘要 癌症免疫治疗正在成为通过靶向治疗癌症的新范式 而不是肿瘤。几种检查点抑制剂的临床批准（例如， Ipilimumab，Pembrolizumab）在一小部分黑色素瘤患者中显示出持久的反应 而不是传统的化疗。尽管取得了这些成功，但许多癌症的免疫原性很差 并且不能产生足够的细胞毒性T淋巴细胞（CTL）， 从免疫检查点疗法中获益。本申请的长期目标是建立 STING激活聚合物纳米疫苗用于黑色素瘤的细胞毒性T细胞治疗。我们将利用 发现了一种超pH敏感聚合物（PC 7A）， 树突状细胞中肿瘤抗原（Ag）的胞质递送的协调和对肿瘤细胞的先天刺激 肿瘤特异性CTL的稳健产生。Ag-PC 7A NP的简单物理混合物产生了 稳健的Th 1和CTL（>80%）应答而不需要先天刺激物（即，CpG，Poly（I：C））。使用 的肿瘤相关抗原（TAA）已显示出显着增加的抗肿瘤疗效， 小鼠中的B16 F10黑素瘤模型。我们将测试中心假设，即PC 7A纳米颗粒疫苗 将与检查点抑制协同作用，以允许黑色素瘤的安全和有效的T细胞疗法。 具体目标有三：（1）将纳米疫苗平台扩展到多种黑色素瘤肽 （2）评价聚合物纳米疫苗在健康、免疫活性 （3）评价聚合物纳米疫苗的抗肿瘤功效及其与药物的协同作用。 检查点抑制上述目标的实现将为临床提供关键数据 用于黑色素瘤治疗的纳米疫苗的翻译。我们还将与其他 nanoalliance成员测试PC 7A NP在其他癌症适应症中的作用。

Abstract Cancer immunotherapy is emerging as a new paradigm for the treatment of cancer by targeting the body's immune system instead of tumor. Clinical approvals of several check point inhibitors (e.g., Ipilimumab, Pembrolizumab) have shown durable response in a small subset of melanoma patients over conventional chemotherapy. Despite these successes, many cancers are poorly immunogenic and do not generate adequate cytotoxic T lymphocytes (CTLs) and therefore these patients cannot benefit from immune checkpoint therapies. The long-term goal of this application is to establish STING-activating polymeric nanovaccines for cytotoxic T cell therapy of melanoma. We will capitalize on the discovery of an ultra-pH sensitive polymer (PC7A) that allows optimal spatio-temporal orchestration of cytosolic delivery of tumor antigen (Ag) in dendritic cells and innate stimulation for the robust production of tumor-specific CTLs. A simple physical mixture of Ag-PC7A NP resulted in a robust Th1 and CTL (>80%) response without the need of innate stimulants (i.e., CpG, Poly(I:C)). Use of tumor associated antigens (TAAs) have shown significantly increased antitumor efficacy in a B16F10 melanoma model in mice. We will test the central hypothesis that PC7A nanoparticle vaccine will synergize with checkpoint inhibition to allow a safe and efficacious T cell therapy of melanoma. There are three specific aims: (1) Expand the nanovaccine platform to multiple melanoma peptide antigens; (2) Evaluate the safety of the polymeric nanovaccines in healthy, immunocompetent animals; and (3) Evaluate the antitumor efficacy of the polymer nanovaccines and its synergy with checkpoint inhibition. Accomplishments of the above aims will provide critical data for clinical translation of the nanovaccines for melanoma therapy. We will also collaborate with other nanoalliance members to test the PC7A NP in additional cancer indications.