Preexisting Levels of CD4 T Cells Expressing PD-1 Are Related to Overall Survival in Prostate Cancer Patients Treated with Ipilimumab
Preexisting Levels of CD4 T Cells Expressing PD-1 Are Related to Overall Survival in Prostate Cancer Patients Treated with Ipilimumab
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DOI：
10.1158/2326-6066.cir-14-0227
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发表时间：
2015-09-01
影响因子：
10.1
通讯作者：
Fong, Lawrence
中科院分区：
文献类型：
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作者：
Kwek, Serena S.;Lewis, Jera;Fong, Lawrence
细胞毒性T淋巴细胞相关抗原-4（CTLA-4）阻断可诱导肿瘤消退并提高癌症患者的生存率。这种治疗可以在没有外源性疫苗的情况下增强适应性免疫应答，但与癌症患者临床结局改善相关的免疫学生物标志物尚未完全建立。在转移性去势抵抗性前列腺癌患者中进行了一项Ib期试验，将伊匹单抗与沙格司亭（GM-CSF）联合使用。除了评估ipilimumab剂量外，还对患者进行临床随访，以了解反应和总生存期以及循环T细胞的免疫调节。在≥ 3 mg/kg/剂的剂量下观察到PSA下降≥ 50%和放射学反应。临床反应的时间可以是立即的或延迟的。在停止治疗后也观察到持久缓解。一部分患者长期生存，有或无客观临床应答。回顾性分析外周血T细胞表型与总生存率的关系。我们发现，治疗诱导了CD 4（+）效应T（T-eff）细胞、调节性T细胞、PD-1（+）CD 4 T-eff细胞和PD-1（+）CD 8 T细胞水平的增加。然而，这些增加的水平与总生存期无关。相反，低的PD-1（+）CD 4 T-eff细胞治疗前基线水平与较长的总生存期相关。此外，总生存期较短的患者的PD-1（+）CD 4 T-eff细胞基线水平高于无癌症男性对照受试者。这些结果表明，免疫检查点标记物PD-1在CD 4 T-eff细胞上的预先存在的表达可能有助于识别可能受益于易普利姆玛治疗的患者。(C)2015年AACR。
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade can induce tumor regression and improved survival in cancer patients. This treatment can enhance adaptive immune responses without an exogenous vaccine, but the immunologic biomarkers associated with improved clinical outcome in cancer patients are not fully established. A phase Ib trial in patients with metastatic, castration-resistant prostate cancer was performed combining ipilimumab with sargramostim (GM-CSF). In addition to evaluating ipilimumab dose, patients were followed clinically for response and overall survival, and for immunomodulation of circulating T cells. PSA declines of >= 50% and radiographic responses were observed at doses of >= 3 mg/kg/dose. Timing of clinical responses could be either immediate or delayed. Durable responses were also observed off treatment. A subset of patients experienced long-term survival with or without objective clinical responses. The relationship between T-cell phenotype in peripheral blood and overall survival was examined retrospectively. We found that the treatment induced an increase in the levels of CD4(+) effector T (T-eff) cells, regulatory T cells, PD-1(+) CD4 T-eff cells, and PD-1(+) CD8 T cells. However, these increased levels were not associated with overall survival. Instead, low pretreatment baseline levels of PD-1(+) CD4 T-eff cells were found to correlate with longer overall survival. Furthermore, baseline levels of PD-1(+) CD4 T-eff cells from patients with shorter overall survival were higher than from cancer-free male control subjects. These results suggest that preexisting expression of immunologic checkpoint marker PD-1 on CD4 T-eff cells may help identify patients that may benefit from ipilimumab treatment. (C) 2015 AACR.