Two cases of intrahepatic cholangiocellular carcinoma with high insertion-deletion ratios that achieved a complete response following chemotherapy combined with PD-1 blockade

Abstract

Background Insertion–deletion mutations (indels) may generate more tumour-specific neoantigens with high affinity to major histocompatibility complex class I. A high indel ratio is also related to a good response to programmed death-1 (PD-1) checkpoint blockade in melanoma and renal cell carcinoma. However, the correlation between a high indel ratio and the immunotherapy response in intrahepatic cholangiocarcinoma (ICC) is unknown. Case presentation Two patients with relapsed ICC at stage IIIb were treated with PD-1 blockade combined with chemotherapy. After 7 and 4 months of chemotherapy and PD-1 blockade (3 and 15 cycles, and 5 and 6 cycles, respectively), magnetic resonance imaging and positron emission tomography with computed tomography imaging showed that both patients achieved a complete response (CR), which has lasted up to nearly 16 and 13 months to date, respectively. Whole-exome sequencing and immunohistochemistry analysis showed that both patients had cancers with microsatellite stability (MSS) and mismatch repair (MMR) proficiency, weak PD-L1 expression, and a tumour mutation burden (TMB) of 2.95 and 7.09 mutations/Mb, respectively. Patient 2 had mutations of TP53 and PTEN that are known to confer sensitivity to immunotherapy, and the immunotherapy-resistant mutation JAK2 , whereas patient 1 had no known immunotherapy response-related mutations. However, the indel ratios of the two patients (48 and 66.87%) were higher than the median of 12.77% determined in a study of 71 ICC patients. Moreover, comparison to six additional ICC patients who showed a partial response, stable disease, or progressive disease after PD-1 blockade treatment alone or in combination with chemotherapy demonstrated no difference in PD-L1 expression, TMB, MSI, and MMR status from those of the two CR patients, whereas the indel frequency was significantly higher in the CR patients. Conclusions These two cases suggest that indels might be a new predictor of PD-1 blockade response for ICC patients beside PD-L1 expression, TMB, MSI, and dMMR, warranting further clinical investigation. Electronic supplementary material The online version of this article (10.1186/s40425-019-0596-y) contains supplementary material, which is available to authorized users.

Local and abscopal responses in advanced intrahepatic cholangiocarcinoma with low TMB, MSS, pMMR and negative PD-L1 expression following combined therapy of SBRT with PD-1 blockade

“…Furthermore, the combination of lenvatinib with pembrolizumab or nivolumab achieved an overall response rate (ORR) of 21.4% and DCR of 92.9% in 14 Stage IV ICC patients who had more than two lines of anticancer therapy, and high TMB was strongly associated with a better therapeutic response [19]. Combined therapy of PD-1 blockade with chemotherapy emerged very recently as a new option for advanced or recurrent ICC, and a few case reports showed promising results: patients with high TMB or high INDEL mutation frequency achieved marked response to the combined therapy [32, 33]. It appeared that ICC patients with high TMB, MSI-H, dMMR and/or PD-L1 positive expression can benefit from immunotherapy or its combination with targeted therapy or chemotherapy.…”

Systemic therapies for intrahepatic cholangiocarcinoma

“…53,54 These findings are supported by case reports, which also detail profound and prolonged responses to ICIs in patients with CCA and known MSI or MMR deficiency, high TMB, or high rates of insertion or deletion mutations, which can result in neoantigens. [77][78][79][80][81] However, in microsatellite-stable, non-MMR deficient CCA, the ORR to ICI monotherapy appears much lower, though data are mixed. To date, KEYNOTE-158 (NCT02628067) is the largest study of ICI monotherapy with pembrolizumab; it includes patients with advanced biliary cancers without known MMR deficiency, after progression on or intolerance to at least 1 line of standard therapy.…”

PD-1/PD-L1 expression profiles within intrahepatic cholangiocarcinoma predict clinical outcome

“…One previous study has revealed that PD-1/PD-L1 was overexpressed in ICC, and the expression of PD-L1 in the frontier of tumors was associated with a 60% reduction in survival [ 19 ]. One case report shows that two recent ICC patients achieved complete remission after PD-1 blockade [ 20 ]. In the tumor microenvironment of ICC, there is limited research on the clinical impact of immune cells such as macrophages, lymphocytes, and immune checkpoints.…”