Phase Ib/II study of safety and efficacy of low-dose decitabine-primed chemoimmunotherapy in patients with drug-resistant relapsed/refractory alimentary tract cancer.
Phase Ib/II study of safety and efficacy of low-dose decitabine-primed chemoimmunotherapy in patients with drug-resistant relapsed/refractory alimentary tract cancer.
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低剂量地西他滨引发的化学免疫疗法治疗耐药复发/难治性消化道癌患者的安全性和有效性的 Ib/II 期研究
DOI：
10.1002/ijc.31531
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发表时间：
2018-09-15
影响因子：
6.4
通讯作者：
Han W
中科院分区：
文献类型：
--
作者：
Chen M;Nie J;Liu Y;Li X;Zhang Y;Brock MV;Feng K;Wu Z;Li X;Shi L;Li S;Guo M;Mei Q;Han W
改善治疗结果的迫切需要为确定消化道（AT）癌症治疗的有效策略提供了良好的理论依据。低剂量地西他滨对化疗和免疫治疗的潜在再敏感性在临床前和之前的I期试验中都很明显。我们进行了一项Ib/II期试验，评估低剂量地西他滨启动的化疗免疫治疗对耐药复发/难治性（R/R）食管癌、胃癌或结直肠癌患者的疗效。45例患者接受了为期5天的地西他滨治疗，随后再给予先前的耐药化疗（地西他滨启动化疗，D‐C队列）或上述方案，然后根据其治疗史进行细胞因子诱导的杀伤细胞治疗（D‐C和细胞因子诱导的杀伤[CIK]细胞治疗，D‐C + CIK队列）。45例患者中有11例（24.4%）报告了3至4级不良事件（ae）。所有ae都是可控的，没有患者发生与治疗相关的死亡。客观缓解率（ORR）和疾病控制率（DCR）分别为24.44%和82.22%，其中2例患者达到持久完全缓解。临床反应可能与无治疗间隔时间和初始手术切除史有关。在D - C + CIK队列中，ORR和DCR分别达到28%和92%。一致地，D - C + CIK队列的无进展生存期（PFS）优于预耐药未启动治疗的最佳PFS （p = 0.0001）。毒性和orr在癌症类型和治疗队列之间无显著差异。地西他滨对化学免疫治疗的再增敏的安全性和有效性是有吸引力和前景的。这些数据为进一步对晚期耐药R/R AT癌症患者进行大规模评估提供了依据。有什么新鲜事吗?化疗是消化道癌症患者的主要治疗选择，但固有或获得性耐药仍然是一个问题。临床前和I期试验表明，低剂量地西他滨对化疗和免疫治疗具有潜在的再敏感性。在这个Ib/II期试验中，低剂量地西他滨启动化疗加/不加细胞因子诱导的杀伤细胞治疗用于耐药复发/难治性AT癌症患者。与预耐药未启动的PFS相比，epi -化学免疫疗法表现出高的应答率和延长的无进展生存期（PFS）。这种疗法的耐受性一般都很好。地西他滨对化学免疫治疗的再增敏的安全性和有效性使其成为一种有前景的治疗策略。
The pressing need for improved therapeutic outcomes provides a good rationale for identifying effective strategies for alimentary tract (AT) cancer treatment. The potential re‐sensitivity property to chemo‐ and immunotherapy of low‐dose decitabine has been evident both preclinically and in previous phase I trials. We conducted a phase Ib/II trial evaluating low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory (R/R) esophageal, gastric or colorectal cancers. Forty‐five patients received either the 5‐day decitabine treatment with subsequent readministration of the previously resistant chemotherapy (decitabine‐primed chemotherapy, D‐C cohort) or the aforementioned regimen followed by cytokine‐induced killer cells therapy (D‐C and cytokine‐induced killer [CIK] cell treatment, D‐C + CIK cohort) based on their treatment history. Grade 3 to 4 adverse events (AEs) were reported in 11 (24.4%) of 45 patients. All AEs were controllable, and no patient experienced a treatment‐related death. The objective response rate (ORR) and disease control rate (DCR) were 24.44% and 82.22%, respectively, including two patients who achieved durable complete responses. Clinical response could be associated with treatment‐free interval and initial surgical resection history. ORR and DCR reached 28% and 92%, respectively, in the D‐C + CIK cohort. Consistently, the progression‐free survival (PFS) of the D‐C + CIK cohort compared favorably to the best PFS of the pre‐resistant unprimed therapy (p = 0.0001). The toxicity and ORRs exhibited were non‐significantly different between cancer types and treatment cohort. The safety and efficacy of decitabine‐primed re‐sensitization to chemoimmunotherapy is attractive and promising. These data warrant further large‐scale evaluation of drug‐resistant R/R AT cancer patients with advanced stage disease. What's new? Chemotherapy is the main therapeutic option for alimentary tract (AT) cancer patients, but intrinsic or acquired drug resistance remains an issue. Preclinical and phase I trials have shown the potential re‐sensitivity property to chemo‐ and immunotherapy of low‐dose decitabine. In this phase Ib/II trial, low‐dose decitabine‐primed chemotherapy with/without cytokine‐induced killer cells treatment was assessed in patients with drug‐resistant relapsed/refractory AT cancers. The epi‐ chemoimmunotherapy exhibited high response rates and prolonged the progression‐free survival (PFS), compared to the pre‐resistant unprimed PFS. The regimen was generally well tolerated. The safety and efficacy of decitabine‐primed re‐sensitization to chemoimmunotherapy make it a promising treatment strategy.
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DOI：
10.1038/nrclinonc.2013.42
发表时间：
2013-05
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
通讯作者：
--
细胞因子诱导的杀伤（CIK）细胞：从基础研究到临床转化。
影响因子：
--
作者：
Guo Y;Han W
通讯作者：
Han W
影响因子：
4.1
作者：
Fan H;Lu X;Wang X;Liu Y;Guo B;Zhang Y;Zhang W;Nie J;Feng K;Chen M;Zhang Y;Wang Y;Shi F;Fu X;Zhu H;Han W
通讯作者：
Han W
低剂量 DNA 去甲基化剂通过上调 microRNA-497 靶向癌症干细胞，从而增强癌细胞的化疗敏感性
DOI：
10.1007/s00432-016-2157-9
发表时间：
2016-07-01
影响因子：
3.6
作者：
Liu, Lin;Chen, Lin;Han, Weidong
通讯作者：
Han, Weidong
自体细胞因子诱导杀伤细胞免疫治疗转移性肾癌的随机研究
影响因子：
11.5
作者：
Liu, Liang;Zhang, Weihong;Ren, Xiubao
通讯作者：
Ren, Xiubao