Successful response to the combination of immunotherapy and chemotherapy in cholangiocarcinoma with high tumour mutational burden and PD-L1 expression: a case report

Mou, Haibo; Yu, Lanfang; Liao, Qin; Hou, Xuehua; Wu, Yinfang; Cui, Qiang; Yan, Ning; Ma, Ruobing; Wang, Ling-Jian; Yao, Ming; Wang, Kai

doi:10.1186/s12885-018-5021-2

Cited by 51 publications

(28 citation statements)

References 32 publications

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“…TMB and other markers, including frameshifts and PD-L1 expression, are frequently used in clinical settings due to their strong correlation with anti-PD-L1/PD-1 drug effectiveness [35][36][37][38][39]. In intrahepatic cholangiocarcinoma with poor prognosis, patients with high TMB can even achieve complete remission with anti-PD-1 [40]. High TMB may indicate that new neoantigens can be produced by tumor cells to activate T cells suppressed by immune checkpoints [41,42].…”

Section: Antigen Recognition Initiates the Immune Responsementioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

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Section: Antigen Recognition Initiates the Immune Responsementioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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“…TMB-H has been reported to correlate with the generation of neoantigens and potential clinical responses to immunotherapies (69). Mou et al (70) reported that a Chinese patient with iCCA, TMB-H and a high expression of PD-L1 responded to the combination of chemotherapy and pembrolizumab. In the present study, the association between TMB and gene mutations was analyzed in Chinese patients CCA, which identified that mutations in KMT2C, BRCA2, AXIN2, MAGI2, PBRM1 and SPTA1 were significantly associated with TMB.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive genomic profile of cholangiocarcinomas in China

Shi

Liu

et al. 2020

Oncol Lett

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Cholangiocarcinoma (CCA) is a primary malignancy, which is often diagnosed as locally advanced or metastatic. Previous studies have revealed genomic characteristics of CCA in Western patients, however comprehensive genomic features of CCA in Chinese patients have not been well understood. To explore the specific genomic characteristics of Chinese patients with CCA, a total of 66 patients with CCA, including 44 intrahepatic CCA (iCCA) and 22 extrahepatic CCA (exCCA) cases, were studied. The most commonly altered genes in CCAs were TP53 (62.12%, 41/66), KRAS (36.36%, 24/66), SMAD4 (24.24%, 16/66), TERT (21.21%, 14/66), ARID1A (19.70%, 13/66), CDKN2A (19.70%, 13/66), KMT2C (9.09%, 6/66) and RBM10 (9.09%, 6/66), ERBB2 (7.58%, 5/66) and BRAF (7.58%, 5/66). Many gene mutations, including STK11, CCND1 and FGF19, were only found in iCCA. RBM10 mutations were found to be significantly higher in exCCA. The gene mutations of neurofibromin 1, STK11, CCND1 and FBXW7 specifically occurred in males, whereas gene mutations of ERBB2, AXIN2 and CREBBP specifically occurred in females. ERBB2 mutations were significantly associated with the sex of patients with CCA. Mutations in PIK3CA, FGFR2 and ZNF750 were significantly associated with the age of patients with CCA and TERT mutations were significantly associated with tumor differentiation. Alterations in KMT2C, PBRM1, AXIN2, MAGI2, BRCA2 and SPTA1 were associated with tumor mutational burden. The findings of the present study suggest that targeted sequencing, using next-generation sequencing technology, provides comprehensive and accurate information on genomic alterations, which will provide novel potential biomarkers for the diagnosis of CCA and may guide precise therapeutic strategies for Chinese patients with CCA.

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“…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.…”

Section: Tumour Immune Microenvironmentmentioning

confidence: 99%

Systemic therapies for intrahepatic cholangiocarcinoma

Kelley

Bridgewater

Gores

et al. 2020

Journal of Hepatology

252

192

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Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal hepatobiliary neoplasm whose incidence is increasing. Largely neglected for decades as a rare malignancy and frequently misdiagnosed as carcinoma of unknown primary, considerable clinical and investigative attention has recently been focused on iCCA worldwide. The established standard of care includes first-line (gemcitabine and cisplatin), second-line (FOLFOX) and adjuvant (capecitabine) systemic chemotherapy. Compared to hepatocellular carcinoma, iCCA is genetically distinct with several targetable genetic aberrations identified to date. Indeed, FGFR2 and NTRK fusions, and IDH1 and BRAF targetable mutations have been comprehensively characterised and clinical data is emerging on targeting these oncogenic drivers pharmacologically. Also, the role of immunotherapy has been examined and is an area of intense investigation. Herein, in a timely and topical manner, we will review these advances and highlight future directions of research.

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Successful response to the combination of immunotherapy and chemotherapy in cholangiocarcinoma with high tumour mutational burden and PD-L1 expression: a case report

Cited by 51 publications

References 32 publications

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Comprehensive genomic profile of cholangiocarcinomas in China

Systemic therapies for intrahepatic cholangiocarcinoma

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