Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.
Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.
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DOI：
10.1038/nature14320
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发表时间：
2015-03-19
期刊：
影响因子：
64.8
通讯作者：
Sampson JH
中科院分区：
文献类型：
--
作者：
Mitchell DA;Batich KA;Gunn MD;Huang MN;Sanchez-Perez L;Nair SK;Congdon KL;Reap EA;Archer GE;Desjardins A;Friedman AH;Friedman HS;Herndon JE 2nd;Coan A;McLendon RE;Reardon DA;Vredenburgh JJ;Bigner DD;Sampson JH
在刺激后，树突状细胞（DC）成熟并迁移到引流淋巴结以诱导免疫应答。因此，离体产生的自体DC已经用肿瘤抗原脉冲并作为免疫疗法注射回患者体内。虽然DC疫苗在治疗包括胶质母细胞瘤（GBM）在内的晚期癌症患者方面表现出有限的前景，但决定DC疫苗疗效的因素仍然知之甚少。在这里，我们证明，预处理的疫苗部位与一个强大的回忆抗原，如破伤风/白喉（Td）类毒素，可以显着提高淋巴结归巢和肿瘤抗原特异性树突状细胞的功效。为了评估疫苗位点预处理对人类的影响，我们将GBM患者随机分组，在双侧接种巨细胞病毒pp 65 RNA脉冲的DC之前，单侧用成熟DC或Td预处理。我们和其他实验室已经表明，pp 65在> 90%的GBM标本中表达，但不在正常大脑周围，这为颠覆这种病毒蛋白作为肿瘤特异性靶标提供了无与伦比的机会。给予Td的患者双侧DC迁移增强，生存率显著提高。在小鼠中，Td预处理还以依赖于趋化因子CCL 3的方式增强双侧DC迁移并抑制肿瘤生长。我们在小鼠中的临床研究和确证性调查表明，用有效的回忆抗原进行预处理可能是改善抗肿瘤免疫治疗的可行策略。
Upon 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 tumor 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 (GBM), the factors dictating DC vaccine efficacy remain poorly understood. Here we demonstrate 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 tumor antigen-specific DCs. To assess the impact of vaccine site pre-conditioning in humans, we randomized patients with GBM to pre-conditioning with mature DCs or Td unilaterally before bilateral vaccination with Cytomegalovirus pp65 RNA-pulsed DCs. We and other laboratories have shown that pp65 is expressed in > 90% of GBM specimens but not surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumor-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 tumor 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 antitumor immunotherapy.