Angiotensin Blockade Modulates the Activity of PD1/L1 Inhibitors in Metastatic Urothelial Carcinoma.
Angiotensin Blockade Modulates the Activity of PD1/L1 Inhibitors in Metastatic Urothelial Carcinoma.
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DOI：
10.1016/j.clgc.2021.04.002
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发表时间：
2021-12
影响因子：
3.2
通讯作者：
Sonpavde G
中科院分区：
文献类型：
--
作者：
Jain RK;Skelton Iv WP;Pond GR;Naqvi M;Kim Y;Curran C;Freeman D;Nuzzo PV;Alaiwi SA;Nassar AH;Jain RK;Sonpavde G
我们假设同时使用血管紧张素转换酶抑制剂（ACEIs）和血管紧张素受体阻滞剂（ARB）可通过下调转化生长因子β（PD 1/L1抑制剂耐药机制）改善接受PD 1/L1抑制剂治疗的转移性尿路上皮癌患者的结局。这项共279例患者的回顾性研究表明，ACEI/ARB与PD 1/L1抑制剂对转移性尿路上皮癌具有潜在的相加或协同作用。肾素-血管紧张素系统参与血管生成和细胞增殖的调节。血管紧张素抑制剂可能通过下调转化生长因子（TGF）-β部分地增强肿瘤灌注来改善药物递送。由于TGF-β与接受程序性细胞死亡蛋白1/程序性细胞死亡配体1（PD 1/L1）抑制剂治疗的转移性尿路上皮癌（mUC）患者的耐药相关，因此我们假设血管紧张素转换酶抑制剂（ACEIs）和血管紧张素受体阻滞剂（ARB）可能改善接受PD 1/L1抑制剂治疗的mUC患者的结局。获得了接受PD 1/L1抑制剂单药治疗的mUC患者的数据;来自Dana-Farber癌症研究所的患者构成了发现数据集，来自Moffitt癌症中心的数据作为验证数据集。Logistic回归分析了在控制预后因素后，ACEI/ARB联合治疗对肿瘤消退（ART）的影响。从发现数据集中获得了178例患者的数据，其中153例（86%）既往接受过铂类药物治疗，33例（18.5%）同时接受过ACEIs/ARB治疗。多变量logistic回归分析显示，ACEIs/ARB与ART发生概率更高相关（比值比[OR] = 2.69; 95%置信区间[CI]，1.15-6.30; P = 0.022）。在验证数据集中，101例患者可用，其中59例（58.4%）既往接受过铂类药物治疗，22例（21.8%）同时接受过ACEIs/ARB治疗。在验证数据集的多变量分析中，ACEI/ARB显示出与ART相关的趋势（OR = 3.28; 95%CI，0.98-10.99; P = 0.054）。在接受PD 1/L1抑制剂治疗的mUC患者中，同时使用血管紧张素阻滞剂与肿瘤消退率较高相关。在前瞻性试验中需要验证，特别是考虑到ACEI/ARB的成本效益。
We hypothesized that concurrent angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) would improve outcomes in patients with metastatic urothelial carcinoma receiving PD1/L1 inhibitors by downregulating transforming growth factor β, a mechanism of resistance to PD1/L1 inhibitors. This retrospective study totaling 279 patients suggests potential additive or synergistic activity of ACEI/ARB with PD1/L1 inhibitors for metastatic urothelial carcinoma. The renin–angiotensin system is involved in the regulation of angiogenesis and cell proliferation. Angiotensin inhibition may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Because TGF-β is associated with resistance in patients with metastatic urothelial carcinoma (mUC) receiving programmed cell death protein 1/programmed cell death ligand 1 (PD1/L1) inhibitors, we hypothesized that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may enhance the outcomes of patients with mUC who receive PD1/L1 inhibitors. Data from patients with mUC who received PD1/L1 inhibitors as monotherapy were obtained; patients from the Dana-Farber Cancer Institute constituted the discovery dataset, and data from Moffitt Cancer Center served as the validation dataset. A logistic regression investigated the impact of concurrent ACEI/ARB primarily on any regression of tumor (ART) after controlling for prognostic factors. Data were available for 178 patients from the discovery dataset, of whom 153 (86%) had received prior platinum and 33 (18.5%) concurrent ACEIs/ARBs. Multivariable logistic regression analysis revealed that ACEIs/ARBs were associated with greater probability of ART (odds ratio [OR] = 2.69; 95% confidence interval [CI], 1.15–6.30; P = .022). In the validation dataset, 101 patients were available, of whom 59 (58.4%) had received prior platinum and 22 (21.8%) concurrent ACEIs/ARBs. ACEI/ARB demonstrated a trend for association with ART (OR = 3.28; 95% CI, 0.98–10.99; P = .054) on multivariable analysis of the validation dataset. Concurrent angiotensin blockade was associated with a higher rate of tumor regression in patients with mUC receiving PD1/L1 inhibitors. Validation is warranted in a prospective trial, especially given the cost efficacy of ACEIs/ARBs.
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影响因子：
17.1
作者：
Pinter M;Jain RK
通讯作者：
Jain RK
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
五因素预后模型用于接受PD-L1抑制剂的转移性尿路上皮癌的生存。
DOI：
10.1097/ju.0000000000001199
发表时间：
2020-12
期刊：
The Journal of urology
影响因子：
--
作者：
Sonpavde G;Manitz J;Gao C;Tayama D;Kaiser C;Hennessy D;Makari D;Gupta A;Abdullah SE;Niegisch G;Rosenberg JE;Bajorin DF;Grivas P;Apolo AB;Dreicer R;Hahn NM;Galsky MD;Necchi A;Srinivas S;Powles T;Choueiri TK;Pond GR
通讯作者：
Pond GR
铂衰竭后转移性尿路上皮癌的AVELUMAB（标枪实体瘤）：汇总的结果是两个开放标签1期试验的两个膨胀队列的结果。
DOI：
10.1016/s1470-2045(17)30900-2
发表时间：
2018-01
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Patel MR;Ellerton J;Infante JR;Agrawal M;Gordon M;Aljumaily R;Britten CD;Dirix L;Lee KW;Taylor M;Schöffski P;Wang D;Ravaud A;Gelb AB;Xiong J;Rosen G;Gulley JL;Apolo AB
通讯作者：
Apolo AB
影响因子：
45.3
作者：
Massard, Christophe;Gordon, Michael S.;Segal, Neil H.
通讯作者：
Segal, Neil H.