University Hospital and Cancer Center Medical Department 1, Goethe University, Frankfurt, Germany.
Department of Medicine (Gastroenterology), University of Leipzig, Leipzig, Germany.
Oncologist. 2022 Jun 8;27(6):430-e433. doi: 10.1093/oncolo/oyab074.
Photochemical internalization (PCI) is a novel technology for light-induced enhancement of the local therapeutic effect of cancer drugs, utilizing a specially designed photosensitizing molecule (fimaporfin). The photosensitizing molecules are trapped in endosomes along with macromolecules or drugs. Photoactivation of fimaporfin disrupts the endosomal membranes so that drug molecules are released from endosomes inside cells and can reach their therapeutic target in the cell cytosol or nucleus. Compared with photodynamic therapy, the main cytotoxic effect with PCI is disruption of the endosomal membrane resulting in delivery of chemotherapy drug, and not to the photochemical reactions per se. In this study we investigated the effect of PCI with gemcitabine in patients with inoperable perihilar cholangiocarcinoma (CCA).
The in vitro cytotoxic effect of PCI with gemcitabine was studied on two CCA-derived cell lines. In a fimaporfin dose-escalation phase I clinical study, we administered PCI with gemcitabine in patients with perihilar CCA (n = 16) to establish a safe and tolerable fimaporfin dose and to get early signals of efficacy. The patients enrolled in the study had tumors in which the whole length of the tumor could be illuminated from the inside of the bile duct, using an optical fiber inserted via an endoscope (Fig. 1). Fimaporfin was administered intravenously at day 0; gemcitabine (i.v.) and intraluminal biliary endoscopic laser light application on day 4; followed by standard gemcitabine/cisplatin chemotherapy.
Preclinical experiments showed that PCI enhanced the effect of gemcitabine. In patients with CCA, PCI with gemcitabine was well tolerated with no dose-limiting toxicities, and no unexpected safety signals. Disease control was achieved in 10 of 11 evaluable patients, with a clearly superior effect in the two highest dose groups. The objective response rate (ORR) was 42%, including two complete responses, while ORR at the highest dose was 60%. Progression-free survival at 6 months was 75%, and median overall survival (mOS) was 15.4 months, with 22.8 months at the highest fimaporfin dose.
Photochemical internalization with gemcitabine was found to be safe and resulted in encouraging response and survival rates in patients with unresectable perihilar CCA.
光化学内化（PCI）是一种利用特殊设计的光敏分子（fimaporfin）增强癌症药物局部治疗效果的新型技术。光敏分子与大分子或药物一起被捕获在内体中。fimaporfin 的光激活破坏了内体膜，使药物分子从细胞内的内体中释放出来，并能够到达细胞胞质或核中的治疗靶标。与光动力疗法相比，PCI 的主要细胞毒性作用是破坏内体膜导致化疗药物的递送，而不是光化学反应本身。在这项研究中，我们研究了 PCI 联合吉西他滨治疗不可切除的肝门部胆管癌（CCA）患者的效果。
我们研究了 PCI 联合吉西他滨对两种 CCA 衍生细胞系的体外细胞毒性作用。在一项 fimaporfin 剂量递增的 I 期临床试验中，我们对 16 例肝门部 CCA 患者给予 PCI 联合吉西他滨治疗，以确定安全耐受的 fimaporfin 剂量，并获得早期疗效信号。入组该研究的患者的肿瘤长度可以从胆管内用插入内镜的光纤照射到（图 1）。fimaporfin 于第 0 天静脉给药；第 4 天静脉给予吉西他滨和经内镜腔内激光光应用；随后进行标准吉西他滨/顺铂化疗。
临床前实验表明，PCI 增强了吉西他滨的作用。在 CCA 患者中，PCI 联合吉西他滨治疗耐受性良好，无剂量限制毒性，无意外安全信号。11 例可评估患者中有 10 例疾病得到控制，两个最高剂量组的效果明显更好。客观缓解率（ORR）为 42%，包括 2 例完全缓解，而最高剂量组的 ORR 为 60%。6 个月无进展生存率为 75%，中位总生存期（mOS）为 15.4 个月，最高 fimaporfin 剂量组为 22.8 个月。
发现吉西他滨的光化学内化安全有效，可提高不可切除的肝门部 CCA 患者的缓解率和生存率。
