Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer.
Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer.
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DOI：
10.18632/oncotarget.10547
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发表时间：
2016-08-16
期刊：
影响因子：
--
通讯作者：
Beer TM
中科院分区：
文献类型：
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作者：
Graff JN;Alumkal JJ;Drake CG;Thomas GV;Redmond WL;Farhad M;Cetnar JP;Ey FS;Bergan RC;Slottke R;Beer TM
虽然程序性细胞死亡1（PD-1）抑制剂在几种实体瘤中显示出明确的抗肿瘤疗效，但转移性去势抵抗性前列腺癌（mCRPC）男性的既往结果显示无活性证据。在这里，我们报告了在接受抗PD-1抗体pembrolizumab治疗的mCRPC患者中观察到的意外抗肿瘤活性。有Enzalutamide治疗进展证据的患者接受帕博利珠单抗200 mg IV治疗，每3周一次，共4次;帕博利珠单抗加用标准剂量Enzalutamide。入组这项正在进行的II期试验的前10例患者中，有3例患者的前列腺特异性抗原（PSA）迅速降低至≤ 0.2 ng/ml。这3例患者中有2例在进入研究时有可测量的疾病;均达到部分缓解。有3名患者发生了显著的免疫相关不良事件。1例发生2级肌炎，1例发生3级甲状腺功能减退，1例发生2级甲状腺功能减退。这些患者均无反应。3名应答者中有2名接受了基线肿瘤活检。这些活检的免疫组织化学显示存在CD 3+、CD 8+和CD 163+白细胞浸润和PD-L1表达。对两名应答者的遗传分析显示，其中一名应答者存在微卫星不稳定性标记。在这项研究中看到的令人惊讶和强大的反应应该导致重新检查前列腺癌中的PD-1抑制。
While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor efficacy in several solid tumors, prior results in men with metastatic castration resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to ≤ 0.2 ng/ml. Two of these three patients had measurable disease upon study entry; both achieved a partial response. There were three patients with significant immune-related adverse events. One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response. Two of the three responders had a baseline tumor biopsy. Immunohistochemistry from those biopsies showed the presence of CD3+, CD8+, and CD163+ leukocyte infiltrates and PD-L1 expression. Genetic analysis of the two responders revealed markers of microsatellite instability in one. The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer.