Dendritic Cell Vaccination in Conjunction with TLR Agonist Polarizes Interferon Immune Responses Associated with Long-term Survival in Malignant Glioma Patients

Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. Pre-clinical studies demonstrate that toll-like receptor (TLR) agonists can enhance the anti-tumor immune response from cancer vaccines. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a randomized, open-label multi-arm Phase 2 clinical trial to evaluate immune responses and survival in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. Patients were randomized to receive ATL-DC vaccination with either a placebo, a TLR-7/8 agonist (resiquimod, topical 0.2%), or a TLR-3 agonist (poly-ICLC, 20 mcg/kg intramuscular). Peripheral blood was obtained at baseline and following the vaccination cycle for immune monitoring. Mass cytometry, bulk and single-cell RNA sequencing analyses were performed.
Conclusion:
CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased fraction of monocytes and decreased expression of markers associated with dysfunction in CD8 T cells.

自体肿瘤裂解物负载树突状细胞（ATL-DC）疫苗是针对高级别胶质瘤患者的极具潜力的免疫治疗手段，但并非所有患者均能产生应答。临床前研究证实，toll样受体（TLR）激动剂可增强癌症疫苗的抗肿瘤免疫应答。为明确联合或不联合佐剂toll样受体（TLR）激动剂聚-ICLC（poly-ICLC）或瑞喹莫德（resiquimod）的自体肿瘤裂解物负载树突状细胞疫苗的最优组合方案，我们开展了一项随机、开放标签多臂II期临床试验，对23例新诊断或复发的WHO III-IV级恶性胶质瘤患者的免疫应答与生存结局进行评估。患者被随机分配接受ATL-DC疫苗联合安慰剂、TLR-7/8激动剂（瑞喹莫德，局部外用0.2%）或TLR-3激动剂（聚-ICLC，20 mcg/kg肌内注射）。于基线及疫苗接种周期结束后采集外周血样本开展免疫监测。本研究采用了质谱流式细胞术（Mass cytometry）、批量RNA测序及单细胞RNA测序分析技术。
结论：
对患者外周血单个核细胞（PBMCs）的CyTOF分析显示，单核细胞占比升高，且CD8阳性T细胞的功能障碍相关标志物表达水平降低。