Preexisting BCG-Specific T Cells Improve Intravesical Immunotherapy for Bladder Cancer
Preexisting BCG-Specific T Cells Improve Intravesical Immunotherapy for Bladder Cancer
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DOI：
10.1126/scitranslmed.3003586
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发表时间：
2012-06-06
影响因子：
17.1
通讯作者：
Albert, Matthew L.
中科院分区：
文献类型：
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作者：
Biot, Claire;Rentsch, Cyrill A.;Albert, Matthew L.
卡介苗（BCG）膀胱内灌注治疗可有效触发非肌层浸润性膀胱癌患者的炎症反应并成功诱导肿瘤免疫，临床反应率为50 - 70%。治疗的成功依赖于肿瘤切除后不久作为辅助治疗的活BCG的重复滴注;然而，确切的机制仍不清楚。使用一个实验模型，我们证明，在一个单一的滴注，卡介苗可以传播到膀胱引流淋巴结和总理干扰素-γ-生产T细胞。尽管如此，重复滴注活卡介苗对于T细胞强有力地浸润到膀胱中是必要的。在滴注前胃肠外暴露于BCG克服了这一要求;与标准方案相比，在第一次膀胱内滴注后，BCG引发了更强烈的急性炎症过程并加速了T细胞进入膀胱。此外，膀胱内治疗原位肿瘤前肠外暴露于BCG显著改善了对治疗的反应。事实上，对BCG具有持续免疫力的患者显示出无复发生存率的显著改善。总之，这些数据表明，监测患者对纯化蛋白衍生物的反应，并且在缺乏纯化蛋白衍生物的情况下，在膀胱内治疗开始之前通过肠胃外暴露来增强BCG反应，可能是改善膀胱内BCG诱导的临床反应的安全有效的手段。
Therapeutic intravesical instillation of bacillus Calmette-Guerin (BCG) is effective at triggering inflammation and eliciting successful tumor immunity in patients with non-muscle invasive bladder cancer, with 50 to 70% clinical response. Therapeutic success relies on repeated instillations of live BCG administered as adjuvant therapy shortly after tumor resection; however, the precise mechanisms remain unclear. Using an experimental model, we demonstrate that after a single instillation, BCG could disseminate to bladder draining lymph nodes and prime interferon-gamma-producing T cells. Nonetheless, repeated instillations with live BCG were necessary for a robust T cell infiltration into the bladder. Parenteral exposure to BCG before instillation overcame this requirement; after the first intravesical instillation, BCG triggered a more robust acute inflammatory process and accelerated T cell entry into the bladder, as compared to the standard protocol. Moreover, parenteral exposure to BCG before intravesical treatment of an orthotopic tumor markedly improved response to therapy. Indeed, patients with sustained preexisting immunity to BCG showed a significant improvement in recurrence-free survival. Together, these data suggest that monitoring patients' response to purified protein derivative, and, in their absence, boosting BCG responses by parenteral exposure before intravesical treatment initiation, may be a safe and effective means of improving intravesical BCG-induced clinical responses.