Ludwig Center for Metastasis Research, The University of Chicago, 5758 South Maryland Avenue, MC 9006, Chicago, IL 60637, United States; Department of Molecular Genetics and Cellular Biology, The University of Chicago, 929 East 57th Street, GCIS W519, Chicago, IL 60637, United States.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
J Control Release. 2017 Nov 28;266:248-255. doi: 10.1016/j.jconrel.2017.09.043. Epub 2017 Oct 5.
Along with vaccines and checkpoint blockade, immune adjuvants may have an important role in tumor immunotherapy. Oligodeoxynucleotides containing unmethylated cytidyl guanosyl dinucleotide motifs (CpG ODN) are TLR9 ligands with attractive immunostimulatory properties, but intratumoral administration has been required to induce an effective anti-tumor immune response. Following on recent studies with radiation-targeted delivery of nanoparticles, we examined enhanced tumor-specific delivery of amphiphile-CpG, an albumin-binding analog of CpG ODN, following systemic administration 3days after tumor irradiation. The combination of radiation and CpG displayed superior tumor control over either treatment alone. Intravital imaging of fluorescently labeled amphiphilic-CpG revealed increased accumulation in irradiated tumors along with decreased off-target accumulation in visceral organs. Within 48h after amphiphile-CpG administration, immune activation could be detected by increased Granzyme B and Interferon gamma activity in the tumor as well as in circulating monocytes and activated CD8 T cells. Using radiotherapy to enhance the targeting of CpG to tumors may help advance this once promising therapy to clinical relevance.
与疫苗和检查点阻断剂一起，免疫佐剂在肿瘤免疫治疗中可能具有重要作用。含有未甲基化胞苷鸟苷二核苷酸基序的寡脱氧核苷酸（CpG ODN）是 TLR9 配体，具有有吸引力的免疫刺激特性，但需要瘤内给药才能诱导有效的抗肿瘤免疫反应。在最近的研究中，我们对纳米颗粒进行了放射靶向递药，研究了在肿瘤照射后 3 天系统给予脂肽-CpG（CpG ODN 的白蛋白结合类似物）后，增强肿瘤特异性递药。与单独治疗相比，辐射和 CpG 的联合治疗显示出更好的肿瘤控制效果。荧光标记的两亲性-CpG 的活体成像显示，在辐照肿瘤中积累增加，同时内脏器官中的非靶标积累减少。在给予脂肽-CpG 后 48 小时内，通过肿瘤以及循环单核细胞和激活的 CD8 T 细胞中颗粒酶 B 和干扰素 γ 活性的增加，可以检测到免疫激活。使用放射疗法增强 CpG 对肿瘤的靶向性，可能有助于将这一曾经有前途的疗法推向临床相关性。
