Photochemical internalization and gemcitabine combined with first-line chemotherapy in perihilar cholangiocarcinoma: observations in three patients

Abstract

Photochemical internalization (PCI) is a technology to induce a localized, intracellular enhancement of therapeutics that are processed through endosomal pathways, including gemcitabine in malignant cells. In addition to a direct phototoxic and tumoricidal effect, PCI specifically disrupts endosomal membranes and, thereby, the compartmentalization of certain cytotoxic compounds to enhance a drug’s intended intracellular target reach within the tissue treated.

Non-resectable extrahepatic cholangiocarcinoma (eCCA) is a common primary tumor and gemcitabine/cisplatin chemotherapy is widely considered standard of care for it. PCI is well suited as an endoscopic intervention, and clinical observations in three subjects participating in a phase I/IIa dose escalation safety trial are described. The trial included patients with perihilar, non-resectable CCA suitable for standard-of-care chemotherapy. Per protocol, a single endoscopic PCI procedure with gemcitabine was conducted at the initiation of standard gemcitabine/cisplatin therapy. Sixteen patients enrolled in the initial dose escalation phase of the trial, which later was extended to explore the safety of a second PCI procedure during chemotherapy.

While limited to a case series, the various clinical observations described here serve to illustrate the effects of localized, perihilar tumor targeting in appropriate patients by any safe methodology, including PCI. As previously indicated by clinical data using other localized treatment modalities, adding a directed, tumor-targeting treatment to systemic therapy to ameliorate the progressively expanding extrahepatic tumor burden can have important effects on the overall outcome of systemic treatment in many patients who have incurable eCCA.

Publication History

Received: 06 March 2020

Accepted: 17 August 2020

Article published online:
27 November 2020

• References

• 1 Banales JM, Cardinale V, Carpino G. et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol 2016; 13: 261-280
• 2 Esnaola NF, Meyer JE, Karachristos A. et al. Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma. Cancer 2016; 122: 1349-1369
• 3 Valle JW, Furuse J, Jitlal M. et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol 2014; 25: 391-398
• 4 Agostinis P, Berg K, Cengel KA. et al. Photodynamic therapy of cancer: An update. CA Cancer J Clin 2011; 61: 250-281
• 5 Selbo PK, Weyergang A, Hogset A. et al. Photochemical Internalisation provides time-and space-controlled endolysosomal escape of therapeutic molecules. J Controlled Release 2010; 148: 2-12
• 6 Sultan AA, Jerjes W, Berg K. et al. Disulfonated tetraphenyl chlorin (TPCS2a)-induced photochemical internalisation of bleomycin in patients with solid malignancies: a phase 1, dose-escalation, first-in-man trial. Lancet Oncol 2016; 17: 1217-1229.
• 7 Ngwa W, Irabor OC, Schoenfeld JD. et al. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer 2018; 18: 313-322
• 8 Wu L, Merath K, Farooq A. et al. Photodynamic therapy may provide a benefit over systemic chemotherapy among non‐surgically managed patients with extrahepatic cholangiocarcinoma. J Surg Oncol 2019; 1-8
• 9 Gonzalez-Carmona MA, Bolch M, Jansen C. et al. Combined photodynamic therapy with systemic chemotherapy for unresectable cholangiocarcinoma. Aliment Pharmacol Ther 2019; 49: 437-447