Combination Immune Checkpoint Inhibitor Therapy is Associated With Increased Blood Pressure in Melanoma Patients.
Combination Immune Checkpoint Inhibitor Therapy is Associated With Increased Blood Pressure in Melanoma Patients.
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免疫检查点抑制剂联合治疗与黑色素瘤患者血压升高有关。
DOI：
10.1161/hypertensionaha.122.20407
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Alexander,MatthewR
中科院分区：
文献类型：
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作者：
Turker,Isik;Sharma,Ananya;Huang,Shi;Johnson,DouglasB;Alexander,MatthewR
高血压是全世界发病率和死亡率的主要危险因素。然而，估计只有20%的高血压患者达到适当的血压控制。此外，在高血压得到控制的人群中，心血管事件的残留风险仍然存在。新出现的证据表明，多种先天和适应性免疫细胞如T淋巴细胞在高血压中起重要作用。免疫检查点抑制剂（ICI）是一种激活T细胞以克服肿瘤免疫逃避的癌症疗法。ICIs包括针对T淋巴细胞抑制受体的单克隆抗体，包括CTLA-4（细胞毒性T淋巴细胞抗原-4）和PD-1（程序性细胞死亡-1）。CTLA-4在慢性刺激后在T细胞上表达，并通过CD28和转导抑制信号阻止共刺激，从而限制T细胞的活化。同样，PD-1在活化的T细胞上表达，与肿瘤细胞上的配体PD-L1和PD-L2结合后，会启动抑制信号，限制T细胞的活化。阻断PD-1 （nivolumab和pembrolizumab）和CTLA-4 （ipilimumab）的ICI疗法促进抗肿瘤T细胞免疫反应，并越来越多地用于各种癌症，包括黑色素瘤，肺癌和肾癌。3 ICI治疗激活T细胞促进肿瘤细胞杀伤；然而，它也会引起T细胞对自身抗原的异常激活，导致免疫相关的不良事件。急性免疫相关不良事件，如肺炎、结肠炎和心肌炎已被很好地描述。慢性免疫相关不良事件描述较少，但据报道影响高达40%的患者，包括停止治疗后。目前尚不清楚ICI治疗是否会改变癌症患者的血压。鉴于T细胞在高血压发病机制中的作用的新证据，我们假设ICI治疗将对癌症患者的血压升高具有慢性作用。根据范德比尔特大学医学中心机构审查委员会的批准，我们在范德比尔特大学医学中心对839例接受ICIs治疗的晚期黑色素瘤患者进行了回顾性队列研究。选择至少有2年可评估随访的患者。比较ICI治疗前和治疗开始后2年门诊就诊基线时的血压读数。排除在门诊就诊时出现无法控制的疼痛或急性严重疾病的患者。我们收集了所有患者的人口统计学变量、ICI类型和持续时间、体重、东部肿瘤合作组表现评分（虚弱程度的测量）、肾功能以及降压药、类固醇和酪氨酸激酶抑制剂药物的数量等数据。基线和2年bp使用配对学生t检验进行比较。为了确定人口统计学和治疗变量与2年血压变化之间的关系，我们使用了多变量线性回归模型。通过可评估的随访，共有259名患者获得了至少2年的生存期（图A）。总的来说，与基线相比，2年的收缩压或舒张压没有明显变化（图A）。然而，在PD-1抑制剂nivolumab和CTLA-4抑制剂ipilimumab联合治疗的患者中，收缩压升高5.5 mm Hg （128.2 vs 133.7 mm Hg， P= 0.011；图B）。无统计学意义
Hypertension is the leading risk factor for morbidity and mortality worldwide. However, only an estimated20% of those with hypertension achieve adequate blood pressure (BP) control. 1 Moreover, a residual risk of cardiovascular events persists in those with controlled hypertension. Emerging evidence suggests an important role for a variety of innate and adaptive immune cells such as T lymphocytes in hypertension. 2 Immune checkpoint inhibitors (ICI) are cancer therapies that activate T cells to overcome tumor immune evasion. ICIs include monoclonal antibodies against inhibitory receptors on T lymphocytes including CTLA-4 (cytotoxic T-lymphocyte antigen-4) and PD-1 (programmed cell death-1). 3 CTLA-4 is expressed on T cells after chronic stimulation and limits T cell activation by preventing costimulation through CD28 and transducing inhibitory signals. Similarly, PD-1 is expressed on activated T cells, and upon binding to ligands PD-L1 and PD-L2 on tumor cells initiates inhibitory signals that limit T cell activation. ICI therapies blocking PD-1 (nivolumab and pembrolizumab) and CTLA-4 (ipilimumab) promote antitumor T cell immune responses and are increasingly used in a variety of cancers including melanoma, lung cancer, and renal cancer. 3 T cell activation by ICI therapy promotes tumor cell killing; however, it can also cause aberrant T cell activation against self-antigens resulting in immune-related adverse events. Acute immune-related adverse events such as pneumonitis, colitis, and myocarditis have been well described. Chronic immune-related adverse events are less well described but have been reported to affect up to 40% of patients, including after discontinuation of therapy. 3, 4 Whether ICI therapy alters BP in cancer patients is unclear. Given emerging evidence for a role of T cells in the pathogenesis of hypertension, we hypothesized that ICI therapy would have chronic effects to increase BP in cancer patients. Following Vanderbilt University Medical Center Institutional Review Board approval, we performed a retrospective cohort study of 839 patients with advanced melanoma treated with ICIs at Vanderbilt University Medical Center. Patients who had at least 2-year evaluable follow-up were selected. BP readings obtained at outpatient clinic visits at baseline prior to ICI therapy and 2 years after therapy initiation were compared. Patients with uncontrolled pain or acute severe illness at the clinic visit based on chart review were excluded. We collected data on demographic variables, ICI type and duration, weight, Eastern Cooperative Oncology Group performance score (measure of frailty), kidney function, and number of antihypertensive, steroid, and tyrosine kinase inhibitor medications on all patients. Baseline and 2-year BPs were compared using a paired Student t test. To determine the relationship between the demographic and treatment variables and the change in BP at 2 years, a multivariable linear regression model was used. A total of 259 individuals who achieved at least 2-year survival with evaluable follow-up were identified (Figure A). Overall, there were no significant changes in systolic or diastolic BP at 2 years compared to baseline (Figure A). However, in those treated with the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab as combination therapy, systolic BP increased by 5.5 mm Hg (128.2 versus 133.7 mm Hg, P= 0.011; Figure B). There were no statistically significant