Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer.
Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer.
复制标题
DOI：
10.18632/oncotarget.4145
复制
发表时间：
2015-07-20
期刊：
影响因子：
--
通讯作者：
Fucikova J
中科院分区：
文献类型：
--
作者：
Podrazil M;Horvath R;Becht E;Rozkova D;Bilkova P;Sochorova K;Hromadkova H;Kayserova J;Vavrova K;Lastovicka J;Vrabcova P;Kubackova K;Gasova Z;Jarolim L;Babjuk M;Spisek R;Bartunkova J;Fucikova J
我们在有资格接受多西他赛联合用灭活LNCaP前列腺癌细胞（DCVAC/PCa）脉冲的自体成熟树突状细胞（DC）治疗的转移性CRPC（mCRPC）患者中进行了一项开放标签、单臂I/II期临床试验。主要和次要终点分别为安全性和免疫应答。作为安全性评价的一部分，将总生存期（OS）与根据Halabi和MSKCC列线图预测的OS进行比较。入组了25例进展性mCRPC患者。治疗包括最初7天给予节拍环磷酰胺50 mg p.o. DCVAC/PCa治疗由12个剂量的中位剂量组成，每个剂量皮下注射1 × 107个树突状细胞。（在注射部位涂抹Aldara乳膏），为期一年。最初2剂DCVAC/PCa以2周间隔给药，随后每3周一次给予多西他赛（75 mg/m2）和泼尼松（5 mg，每日2次），直至观察到毒性或不耐受。然后每6周一次注射DCVAC/PCa，直至一次白细胞分离术生产的最大剂量。未报告严重DCVAC/PCA相关不良事件。中位OS为19个月，而Halabi列线图预测的中位OS为11.8个月，MSKCC列线图为13个月。Kaplan-Meier分析显示，与MSKCC（风险比0.26，95% CI：0.13-0.51）和Halabi（风险比0.33，95% CI：0.17-0.63）预测相比，患者的死亡风险较低。我们观察到外周血中TdR显著降低。DCVAC/PCa的长期施用导致PSA特异性T细胞的诱导和维持。我们没有发现任何与更好的OS显著相关的免疫学参数。在mCRPC患者中，DCVAC/PCa和多西他赛联合化学免疫治疗是安全的，并且生存期长于预期。伴随化疗并不排除特异性抗肿瘤细胞毒性T细胞的诱导。
We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms. Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis. No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13–0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17–0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS. In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.