PDF(Pubmed)
Abstract：
Immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in various tumors. A significant therapeutic challenge with either ICIs or PARP inhibitors as monotherapy is treatment failure from intrinsic primary resistance or the development of secondarily acquired resistance after a period of responsiveness. The combination of PARP inhibitors and ICIs could mitigate this by potentiating treatment response. We describe an 83-year-old male patient who initially presented with abdominal pain, and weight loss along with alternating constipation and diarrhea. Imaging and biopsy revealed metastatic esophageal adenocarcinoma. Genomic testing revealed germline BRCA2 mutation. The patient initially underwent a few cycles of chemoimmunotherapy. However, due to intolerance to chemotherapy, the patient\'s case was discussed at a multidisciplinary molecular tumor board. He was switched to PARP inhibitor olaparib and ICI nivolumab. This combination led to a durable complete response. A combination of poly-ADP ribose polymerase inhibitor (PARPi) plus ICI may work in synergy through various mechanisms including enhanced neoantigen expression, release of immune-activating cytokines, and increased programmed death-ligand 1 expression. This may culminate in accentuated efficacy outcomes with a manageable safety profile. This exceptional response with ICI and PARPi in our case is consistent with the synergistic value of this combination, and prospective studies are warranted to definitively characterize clinical utility.
摘要：
免疫检查点抑制剂(ICIs)和聚(ADP-核糖)聚合酶(PARP)抑制剂已经在各种肿瘤中显示出功效。使用ICIs或PARP抑制剂作为单一疗法的重要治疗挑战是由于固有的原发性抗性或在一段时间的应答性后发展为继发性获得性抗性的治疗失败。PARP抑制剂和ICI的组合可以通过增强治疗反应来减轻这种情况。我们描述了一名83岁的男性患者，最初表现为腹痛，和体重减轻以及交替便秘和腹泻。影像学和活检显示转移性食管腺癌。基因组检测显示种系BRCA2突变。患者最初接受了几个周期的化学免疫疗法。然而,由于对化疗的不耐受，患者的病例在多学科分子肿瘤委员会进行了讨论。他改用PARP抑制剂奥拉帕尼和ICI纳武单抗。这种组合导致了持久的完整响应。聚ADP核糖聚合酶抑制剂（PARPi）加ICI的组合可能通过各种机制协同作用，包括增强的新抗原表达，释放免疫激活细胞因子，和增加程序性死亡配体1表达。这可能最终导致具有可管理的安全性的增强的疗效结果。在我们的案例中，ICI和PARPi的这种特殊反应与这种组合的协同价值是一致的，和前瞻性研究有必要明确表征临床效用。
