Effective Response of Intrahepatic Cholangiocarcinoma to Pembrolizumab: A Case Report.

The efficacy of pembrolizumab for intrahepatic cholangiocellular carcinoma (IHCCC) is not widely reported. We began pembrolizumab treatment in a 69-year-old male with recurrent IHCCC at 18 months after his surgery because of the proven microsatellite instability (MSI)-high status. The patient had partial response, with an 82.5% reduction at the end of 18 courses. Immunostaining of the primary tumor revealed intra-tumoral infiltration of both PD-1+ and CD8+ T cells, and a low expression of PD-L1. Intra-tumoral infiltration of both PD-1+ and CD8+ T cells may be a predictive factor of the efficacy of pembrolizumab. Expression of PD-L1 did not correlate with a therapeutic effect, but the tumor microenvironment of our patient's recurrent lesions may have been modified by conventional chemotherapy and CD8+ T cells.

Nakamura M ，Ueno M ，Hayami S ，Kawai M ，Miyamoto A ，Suzaki N ，Hirono S ，Okada KI ，Miyazawa M ，Kitahata Y ，Kobayashi R ，Kojima F ，Yamaue H ... -  《-》

Inhibition of T-cell-mediated immune response via the PD-1/ PD-L1 axis in cholangiocarcinoma cells.

Cholangiocarcinoma (CCA) is a malignant biliary tract epithelium tumor. The programmed death-1 (PD-1)/programmed receptor-ligand 1 (PD-L1) signaling pathway has been implicated as an immune escape mechanism in several cancers. The present study aimed to assess the expression of PD-L1 on human CCA cell lines and its potential role in suppressing CD8+ T- cell function. A panel of intrahepatic CCA cell lines was evaluated for immune regulatory checkpoint ligands and inflammation markers. Effects of pro-inflammatory cytokine, interferon gamma (IFN-γ), on the expression of immune regulatory checkpoint ligands and inflammation markers were determined. The PD-L1 function was measured by co-culturing CCA cells with lymphocytes. Most of the selected Thai CCA cell lines, including HuCCA-1, RMCCA-1, KKU-100, and KKU-213, expressed higher PD-L1 than normal cholangiocyte MMNK-1 and ANK-1 cells. Both PD-L1 and cyclooxygenase-2 (COX-2) expressions were highest in HuCCA-1 cells. A 48 h treatment with IFN-γ increased the expression of PD-L1 and COX-2 in CCA cells. The expression of CTLA-4 ligands, including H7-1 and H7-2, did not change after IFN-γ treatment. Rofecoxib, a specific COX-2 inhibitor, mitigated IFN-γ-induced PD-L1 expression. After 48 h co-incubation, CD8+ T-cell apoptosis was increased as compared to the control group. Pretreatment of CCA cells with IFN-γ further increased CD8+ T-cell apoptosis. Pembrolizumab, an anti-PD-1 antibody, mitigated CCA cell escape phenomenon. The inhibition of T-cell-mediated immune response via the PD-L1/PD-1 axis are evidenced in intrahepatic CCA. Immunotherapy with checkpoint inhibitor offers a potentially therapeutic strategy for CCA patients; however, further in vivo and clinical studies are required.

Suriyo T ，Fuangthong M ，Artpradit C ，Ungtrakul T ，Sricharunrat T ，Taha F ，Satayavivad J ... -  《-》

Intrahepatic Cholangiocarcinoma with High Microsatellite Instability and Tumor Mutation Burden That Responded Significantly to Pembrolizumab but Perforated within a Short Period.

Yamazaki S ，Kubota K ，Shimizu A ，Notake T ，Umemura K ，Kamachi A ，Goto T ，Tomida H ，Yamashita N ，Sato M ，Kanno H ，Soejima Y ... -  《-》

Microsatellite Instability-high Intrahepatic Cholangiocarcinoma with Portal Vein Tumor Thrombosis Successfully Treated with Pembrolizumab.

Naganuma A ，Sakuda T ，Murakami T ，Aihara K ，Watanuki Y ，Suzuki Y ，Shibasaki E ，Masuda T ，Uehara S ，Yasuoka H ，Hoshino T ，Kudo T ，Ishihara H ，Ogawa T ，Kitamoto Y ，Ogawa A ... -  《-》

Exceptional Response to Pembrolizumab in a Metastatic, Chemotherapy/Radiation-Resistant Ovarian Cancer Patient Harboring a PD-L1-Genetic Rearrangement.

Purpose: Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed.Patients and Methods: We describe a heavily pretreated patient with ovarian cancer with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune checkpoint inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer responder were carefully investigated using immunohistochemistry (IHC), quantitative multiplex fluorescence methods (i.e., automated quantitative analysis, AQUA) and whole-exome sequencing (WES) techniques.Results: The patient harbored a recurrent/metastatic radiation and chemotherapy-resistant high-grade ovarian carcinoma with clear cell features. While progressing on any standard treatment modality, she demonstrated a remarkable complete response to the anti-PD1 immune checkpoint inhibitor pembrolizumab. WES results were notable for the presence a relative low number of mutations (tumor mutation load/Mb = 4.31, total mutations = 164) and a peculiar structural variant disrupting the 3' region of the PD-L1 gene causing aberrant PD-L1 surface expression as confirmed by IHC and AQUA technology. Heavy infiltration of the PD-L1-mutated and PD-L1-overexpressing tumor with T-cell lymphocytes (i.e., CD4+/CD8+ TIL), CD68+ macrophages, and CD20+ B cells was detected in the surgical specimen strongly suggesting immune evasion as a key mechanism of tumor growth and survival. Patient's complete clinical responses remain unchanged at the time of the writing of this report with no significant side effects reported to date.Conclusions: Anti-PD1 inhibitors may represent a novel treatment option for recurrent/metastatic human tumors refractory to salvage treatment harboring PD-L1 gene structural variations causing aberrant PD-L1 expression. Clin Cancer Res; 24(14); 3282-91. ©2018 AACRSee related commentary by Lheureux, p. 3233.

Bellone S ，Buza N ，Choi J ，Zammataro L ，Gay L ，Elvin J ，Rimm DL ，Liu Y ，Ratner ES ，Schwartz PE ，Santin AD ... -  《-》