Medical Oncology Service, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
J Immunother Cancer. 2018 Dec 18;6(1):150. doi: 10.1186/s40425-018-0473-0.
Immune checkpoint inhibitors have revolutionized treatment and improved survival in many cancers. However, since immune-related adverse events (irAEs) are potentially fatal, early recognition and prompt treatment are warranted. One of the rarest but most dramatic irAE is myocarditis, which has significant morbidity and mortality if not recognized and treated early.
To report the first case of myocarditis in a patient with metastatic castration-resistant prostate cancer (mCRPC) treated with a combination of nivolumab, an anti-programmed cell death protein 1 antibody, and PROSTVAC, a vector-based therapeutic prostate cancer vaccine.
A 79-year-old man with mCRPC metastatic to bone and lymph nodes and a history of atrial fibrillation presented with blurred vision and pain and stiffness in the upper back after 8 weeks on a clinical trial with nivolumab (1 mg/kg) and PROSTVAC, both given every 2 weeks. Eye exam was within normal limits, while musculoskeletal exam revealed tenderness in trapezius muscles and decreased motor strength in arms (III/V) and neck (IV/V). The rest of the physical exam was within normal limits, with the exception of an irregular heart rhythm. Laboratory tests were as follows: creatinine kinase (CK) 3200 U/L (normal: 39-308 U/L), CK-MB 65.7 mcg/L (normal: 0-7.6 mcg/L), troponin I 0.209 ng/mL (normal: 0-0.056 ng/mL). Electrocardiogram (ECG) revealed atrial fibrillation with QT prolongation (QTc 514 msec) and left anterior fascicular block, unchanged from baseline. 2D-echocardiogram showed a left ventricular ejection fraction of 65% with an enlarged left atrium, dilated right ventricle, and increased pulmonary artery pressure (45 mmHg). ProBNP was elevated at 1463 pg/mL and peaked at 3066 pg/mL one day after hydration. With a presumed diagnosis of autoimmune myositis and possible myocarditis, the patient was admitted and started on methylprednisolone 1 mg/kg/day. Cardiac MRI showed elevated native myocardial T1 values consistent with myocarditis (Fig. 1). The patient was discharged on a prednisone taper after normalization of cardiac enzymes on day 4. Treatment with PROSTVAC continued for three more months; nivolumab was discontinued. Six months later, patient is doing well, with no residual cardiac damage.
Cardiovascular irAEs are relatively rare (< 1%) and have a variety of clinical presentations. Myocarditis is potentially life-threatening and can range from subclinical to fulminant. Therefore, clinical suspicion, early detection, and prompt treatment are imperative (1). The initial diagnostic workup should include cardiac enzymes, ECG, and 2D-echocardiogram. The most commonly observed ECG changes are generalized repolarization abnormalities, prolonged QT interval, and conduction abnormalities (2). An elevated troponin I in the absence of overt coronary artery disease is suggestive of myocarditis and should be evaluated further. Myocardial biopsy is the standard diagnostic procedure; however, a cardiac MRI can achieve a diagnosis when biopsy is not feasible (3). Advancements in parametric mapping techniques have allowed the use of native myocardial T1 in the detection of myocarditis, as it has superior diagnostic performance and higher sensitivity than older parameters (3). Our patient had been treated with an immune checkpoint inhibitor and a therapeutic cancer vaccine to induce effective antitumor activity through immunogenic intensification and presented with muscle stiffness and elevated CK. Although he had no new cardiovascular symptoms, cardiac enzymes were tested to rule out myocardial involvement. MRI with gadolinium confirmed the diagnosis of myocarditis. To date, none of the 1360 patients treated with PROSTVAC as a single agent have developed myocarditis, while myocarditis has been rarely reported in patients treated with nivolumab (< 1%) (1). Whether the combination of PROSTVAC and nivolumab presents an additional risk of myocarditis is unclear. To our knowledge, this is the first case of myocarditis in a patient with mCRPC receiving simultaneous treatment with an immune checkpoint inhibitor and a prostate cancer vaccine. Our experience highlights the importance of suspicion and early intervention in patients who present with cardiac abnormalities after receiving cancer immunotherapy. We propose following protocol: baseline troponin, ECG, and 2D-echocardiogram prior to treatment, then repeated troponin at 2, 4, and 12 weeks post-treatment, then monthly. If troponin becomes positive without alternative explanation, myocarditis should be ruled out with cardiac MRI or myocardial biopsy, and patient should be admitted for treatment with high-dose steroids as early intervention may minimize myocardial injury.
免疫检查点抑制剂彻底改变了许多癌症的治疗方式并提高了生存率。然而，由于免疫相关不良事件（irAEs）可能是致命的，因此需要早期识别和及时治疗。irAEs 中最罕见但最严重的之一是心肌炎，如果不能早期识别和治疗，其具有显著的发病率和死亡率。
报告首例转移性去势抵抗性前列腺癌（mCRPC）患者在接受纳武单抗（一种抗程序性死亡蛋白 1 抗体）和 PROSTVAC（一种基于载体的前列腺癌治疗疫苗）联合治疗后发生心肌炎的病例。
一名 79 岁男性患有 mCRPC，已转移至骨骼和淋巴结，有房颤病史。在接受纳武单抗（1mg/kg）和 PROSTVAC 每两周一次的临床试验 8 周后，出现视物模糊和上背部疼痛、僵硬。眼部检查正常，而肌肉骨骼检查显示斜方肌压痛和手臂（III/V）和颈部（IV/V）运动力量下降。其余的体检均在正常范围内，除了心律不齐。实验室检查结果如下：肌酸激酶（CK）3200U/L（正常范围：39-308U/L），肌酸激酶同工酶 MB 65.7mcg/L（正常范围：0-7.6mcg/L），肌红蛋白 I 0.209ng/mL（正常范围：0-0.056ng/mL）。心电图（ECG）显示房颤伴 QT 延长（QTc 514msec）和左前束支阻滞，与基线时无变化。二维超声心动图显示左心室射血分数为 65%，左心房增大，右心室扩张，肺动脉压升高（45mmHg）。脑钠肽前体升高至 1463pg/mL，在水化治疗后一天达到峰值 3066pg/mL。考虑自身免疫性肌炎和可能的心肌炎，患者被收入院并开始接受甲泼尼龙 1mg/kg/天治疗。心脏 MRI 显示升高的心肌 T1 固有值，符合心肌炎（图 1）。患者在第 4 天心脏酶正常后开始泼尼松减量治疗。PROSTVAC 治疗继续进行了三个月；纳武单抗被停用。六个月后，患者情况良好，无残留的心脏损伤。
心血管 irAEs 相对罕见（<1%），临床表现多样。心肌炎具有潜在的致命性，可从亚临床到暴发性不等。因此，临床怀疑、早期发现和及时治疗至关重要（1）。初始诊断性检查应包括心脏酶、心电图和二维超声心动图。最常见的心电图变化是广义复极化异常、QT 间期延长和传导异常（2）。在没有明显冠状动脉疾病的情况下，肌红蛋白 I 升高提示心肌炎，应进一步评估。心肌活检是标准诊断程序；然而，当活检不可行时，心脏 MRI 可以进行诊断（3）。参数映射技术的进步使得使用心肌 T1 固有值来检测心肌炎成为可能，因为它比旧参数具有更好的诊断性能和更高的灵敏度（3）。我们的患者接受了免疫检查点抑制剂和治疗性癌症疫苗的联合治疗，以通过免疫强化诱导有效的抗肿瘤活性，表现为肌肉僵硬和 CK 升高。尽管他没有新的心血管症状，但仍检查了心脏酶以排除心肌受累。钆增强 MRI 证实了心肌炎的诊断。迄今为止，作为单一药物治疗的 1360 名接受 PROSTVAC 治疗的患者中没有发生心肌炎，而接受纳武单抗治疗的患者（<1%）中很少有心肌炎报道（1）。PROSTVAC 和纳武单抗联合治疗是否会增加心肌炎的风险尚不清楚。据我们所知，这是首例接受免疫检查点抑制剂和前列腺癌疫苗联合治疗的转移性去势抵抗性前列腺癌患者发生心肌炎。我们的经验强调了在接受癌症免疫治疗后出现心脏异常的患者中保持警惕和早期干预的重要性。我们建议以下方案：在治疗前进行基线肌钙蛋白、心电图和二维超声心动图检查，然后在治疗后 2、4 和 12 周重复肌钙蛋白检查，然后每月检查一次。如果肌钙蛋白呈阳性且无其他解释，应使用心脏 MRI 或心肌活检排除心肌炎，并应入院接受大剂量类固醇治疗，因为早期干预可能会最大限度地减少心肌损伤。
