STING-Activating Polymeric Nanovaccines for T Cell Therapy of Melanoma

摘要 癌症免疫疗法正在成为靶向治疗癌症的新范式 身体的免疫系统而不是肿瘤。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疗效 而不是常规化疗。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)，因此这些患者不能 从免疫检查点疗法中受益。此应用程序的长期目标是建立 用于黑色素瘤细胞毒性T细胞治疗的刺激性聚合物纳米疫苗。我们将利用这一点 关于一种超pH敏感聚合物(PC7A)的发现 树突状细胞胞浆递送肿瘤抗原及天然刺激作用的研究 强劲的肿瘤特异性CTL的产生。Ag-PC7A NP的简单物理混合物导致了 强大的Th1和CTL(&gt；80%)反应，不需要天生的刺激物(即CpG，Poly(I：C))。使用 肿瘤相关抗原(TAA)的研究表明，在一种 小鼠B16F10黑色素瘤模型的建立。我们将检验PC7A纳米颗粒疫苗的中心假设 将与检查点抑制协同作用，以实现安全有效的黑色素瘤T细胞治疗。 具体有三个目标：(1)将纳米疫苗平台扩展到多种黑色素瘤多肽 (2)评价聚合纳米疫苗在健康、有免疫能力的人群中的安全性 动物；和(3)评价聚合物纳米疫苗的抗肿瘤效果及其与 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 纳米联盟成员测试PC7A 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.