浅表性膀胱癌患者膀胱内注入自体干扰素激活巨噬细胞诱导的局部免疫刺激

F. Pagès, S. Lebel‐Binay, Annick Vieillefond, L. Deneux, M. Cambillau, O. Soubrane, B. Debré, D. Tardy, J. Lemonne, J. Abastado, W. Fridman, N. Thiounn
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引用次数: 17

摘要

我们开展了一项I/II期临床试验,研究浅表性膀胱癌患者膀胱内给药自体IFN - γ活化巨噬细胞(MAK)的安全性和有效性。体外制备单核细胞来源的MAK细胞,患者接受6次1·4 × 108至2·5 × 108细胞滴注,每周1次,连续5周。治疗耐受性良好,有7个1级和5个2级不良反应。17例患者中有9例在首次注射MAK后的一年内没有复发。本研究的目的是寻找与MAK局部免疫刺激有关的免疫参数。对患者的监测显示,在注射MAK后,尿IL - 8、GM - CSF和IL - 18(在较小程度上)均增加,且存在个体间差异。尿IL - 8水平比其他细胞因子高约10倍,其生物活性通过尿弹性酶的增加反映出来,表明中性粒细胞活化和脱颗粒。我们还发现,在接受调查的12名患者中,有9名患者在注射MAK 7天后尿中新蝶呤(IFN‐γ‐活化的巨噬细胞的标志物)升高,而血清中新蝶呤水平几乎稳定。这些结果与输注后激活的巨噬细胞在膀胱壁上的持久性一致。此外,在第六次注射MAK 2个月后,尿涂片中有巨噬细胞,巨噬细胞的评分与尿中中性粒细胞的数量相关。总之,本研究为浅表性膀胱癌患者注射MAK这种新颖且安全的免疫治疗方法所诱导的局部免疫刺激提供了证据。
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Local immunostimulation induced by intravesical administration of autologous interferon‐gamma‐activated macrophages in patients with superficial bladder cancer
We conducted a phase I/II clinical trial of the safety and efficacy of intravesical administration of autologous IFN‐γ‐activated macrophages (MAK) in patients with superficial bladder cancer. Monocyte‐derived MAK cells were prepared in vitro and patients received six instillations of 1·4 × 108 to 2·5 × 108 cells, once a week, for five consecutive weeks. Treatment was well tolerated, with seven grade 1 and five Grade 2 protocol‐related adverse effects. Nine out of 17 included patients had no recurrences during the year following the first instillation of MAK. The aim of the present study was to search for immune parameters related to local immunostimulation induced by MAK. Monitoring of the patients showed that urinary IL‐8, GM‐CSF and, to a lesser extent, IL‐18 were increased following MAK instillations, with inter‐individual differences. The urinary IL‐8 level was about 10‐fold higher than that observed for other cytokines, and its biological activity was reflected by a concomitant increase of urinary elastase, indicating neutrophil activation and degranulation. We also showed that nine out of 12 patients investigated presented an increase of urinary neopterin, a marker of IFN‐γ‐activated macrophages, 7 days after MAK instillation, while serum neopterin levels were almost stable. These results are in line with persistence of activated macrophages in the bladder wall after infusions. Moreover, there was evidence of macrophages in urine smears 2 months after the sixth MAK instillation, and the score of macrophages correlated with the quantity of neutrophils in the urine. Overall, this study provides evidence of a local immunostimulation induced by this novel and safe immunotherapeutic approach of MAK instillations in patients with superficial bladder cancer.
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