STM：膀胱内滴注卡介苗治疗膀胱癌新进展

6月4日，Sci. Transl. Med.报道了膀胱内滴注卡介苗（BCG）治疗膀胱癌的研究新进展。膀胱内滴注卡介苗可引发炎症反应，促进抗肿瘤免疫反应。这项治疗对50-70%的无肌肉侵袭膀胱癌患者有临床效果。成功的治疗有赖于肿瘤切除后即给予反复的活卡介苗滴注。但这项治疗的机理一直不明。

利用一项实验模型，研究者证实，一次滴注后BCG可散播到膀胱排泄淋巴结，并诱导生成干扰素γ的T细胞。然而，反复滴注活BCG对有力的T细胞浸润是必须的。如果在滴注BCG前，使患者不经胃肠道途径暴露于BCG，可以免除这种需要。首次膀胱内滴注后，BCG触发了一种有力的急性期炎症反应，并促进T细胞进入膀胱。更重要的是，在滴注BCG前不经胃肠道途径暴露于BCG，可显著增加膀胱肿瘤对这项治疗的反应性。临床结果表明，对BCG具有持续预先存在的免疫性的患者无复发生存率更高。

总之，这项研究提示，在膀胱内滴注BCG治疗之前，进行胃肠外BCG暴露，可安全有效地提高膀胱内滴注BCG对膀胱癌的疗效。

doi:10.1016/j.cell.2011.10.017
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Preexisting BCG-Specific T Cells Improve Intravesical Immunotherapy for Bladder Cancer

Claire Biot1,2,3, Cyrill A. Rentsch1,2,4,*, Joel R. Gsponer1,2,4,*, Frédéric D. Birkh?user5, Hélène Jusforgues-Saklani1,2, Fabrice Lema?tre6,7, Charlotte Auriau1,2, Alexander Bachmann5, Philippe Bousso6,7, Caroline Demangel8, Lucie Peduto9, George N. Thalmann5 and Matthew L. Albert1,2,10,

Therapeutic intravesical instillation of bacillus Calmette-Guérin (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-γ–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.