Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients

摘要

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.%John Sampson及同事报告了对成胶质细胞瘤患者所做的一个小型临床试验，结果显示，对树突细胞免疫接种的免疫和抗肿瘤反应，可以通过用"破伤风/白喉类毒素"(Td)预处理接种点而增强。小鼠实验显示了类似的效应，说明用Td预处理可增强树突细胞向肿瘤的迁移，至少部分是由于细胞因子CCL3的作用。虽然所报告的临床试验是小型的，但这些发现也许为寻找提高抗癌疫苗功效的新方法铺平了道路。