Department of Vaccine Immunology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan; Nebuta Research Institute for Life Sciences, and Center for Brain and Health Sciences, Aomori University, Kohbata 2-3-1, Aomori, 030-0943, Japan.
Department of Vaccine Immunology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Adv Drug Deliv Rev. 2019 Jul;147:37-43. doi: 10.1016/j.addr.2019.07.008. Epub 2019 Jul 11.
Vaccine immunotherapy consisting of tumor antigens combined with an immune-enhancing adjuvant fosters cytotoxic T cell (CTL) proliferation. Clinically, polyI:C has been used as an adjuvant to enhance cancer vaccine protocols. However, according to its long history, polyI:C promotes inflammation that causes cytokine toxicity. Although checkpoint inhibitor immunotherapy has improved the prognoses of patients with progressive cancer, over 75% of patients continue to experience resistance to antibody (Ab) against anti-programmed cell death-protein 1 (PD-1) or its ligand, PD-L1 therapy. In most cases, patients suffer from adverse events resulting from inflammation during anti-PD-1/L1 Ab therapy, which is a serious obstacle to patients' quality of life. We have studied the functional properties of double-stranded (ds)RNA and polyI:C, and developed a nucleic acid adjuvant that barely induces a significant increase in the level of serum inflammatory cytokines in mouse models. This adjuvant, termed ARNAX, consists of DNA-capped dsRNA that specifies the endosomal target for Toll-like receptor 3 (TLR3) in dendritic cells (DCs). We expect that this adjuvant is safe for administration in elderly patients with cancer receiving immunotherapy. Here, we summarize the properties of ARNAX for immunotherapy in mice. We suggest that DC-priming is essential to induce anti-tumor immunity; neither exogenous inflammation nor the administration of tumor antigens is always a prerequisite for DC-mediated CTL proliferation. If our mouse data can be extrapolated to humans, ARNAX and the liberated endogenous tumor antigens may facilitate effect of current therapies on patients with therapy-resistant tumors.
疫苗免疫疗法包括与免疫增强佐剂结合的肿瘤抗原，可促进细胞毒性 T 细胞（CTL）增殖。临床上，聚肌苷酸（polyI:C）已被用作佐剂来增强癌症疫苗方案。然而，根据其悠久的历史，polyI:C 可促进炎症，从而导致细胞因子毒性。尽管检查点抑制剂免疫疗法改善了进展期癌症患者的预后，但超过 75%的患者继续对针对程序性细胞死亡蛋白 1（PD-1）或其配体的抗体（Ab）治疗产生耐药性。在大多数情况下，患者在抗 PD-1/L1 Ab 治疗期间因炎症而遭受不良反应，这严重影响了患者的生活质量。我们研究了双链（ds）RNA 和 polyI:C 的功能特性，并开发了一种核酸佐剂，该佐剂在小鼠模型中几乎不会引起血清炎症细胞因子水平的显著增加。这种佐剂称为 ARNAX，由指定树突状细胞（DC）中 Toll 样受体 3（TLR3）内体靶标的 DNA 封端 dsRNA 组成。我们期望该佐剂对接受免疫疗法的老年癌症患者的给药是安全的。在这里，我们总结了 ARNAX 在小鼠中进行免疫疗法的特性。我们认为，DC 引发对于诱导抗肿瘤免疫至关重要；外源性炎症或肿瘤抗原的给予并不总是 DC 介导的 CTL 增殖的前提条件。如果我们的小鼠数据可以外推到人类，那么 ARNAX 和释放的内源性肿瘤抗原可能会促进当前疗法对耐药性肿瘤患者的疗效。
