Dataset Information

Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial.

ABSTRACT:

Background

A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy.

Methods

Herein, we performed comprehensive molecular characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequencing, RNA sequencing, and correlative analysis. In addition, we performed single-cell RNA sequencing using peripheral blood mononuclear cells.

Results

The overall response rate of pembrolizumab in sorafenib-failed HCC patients was 10% ([6/60] 95% CI, 2.4-17.6). In a univariate analysis using clinicopathological features, female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were identified as contributing factors to pembrolizumab response. Somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that pembrolizumab responders demonstrated T cell receptor (TCR) signaling activation with expressions of MHC genes, indicating increased levels of T cell cytotoxicity. In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, patients with progressive disease showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways.

Conclusions

Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells during pembrolizumab treatment and down-regulation of neutrophil-associated markers, significantly benefited from pembrolizumab treatment.

Trial registration

NCT#03163992 (first posted: May 23, 2017).

SUBMITTER: Hong JY

PROVIDER: S-EPMC8734300 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Publications

Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial.

Hong Jung Yong JY Cho Hee Jin HJ Sa Jason K JK Liu Xiaoqiao X Ha Sang Yun SY Lee Taehyang T Kim Hajung H Kang Wonseok W Sinn Dong Hyun DH Gwak Geum-Youn GY Choi Moon Seok MS Lee Joon Hyeok JH Koh Kwang Cheol KC Paik Seung Woon SW Park Hee Chul HC Kang Tae Wook TW Rhim Hyunchul H Lee Su Jin SJ Cristescu Razvan R Lee Jeeyun J Paik Yong Han YH Lim Ho Yeong HY

Genome medicine 20220106 1

<h4>Background</h4>A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy.<h4>Methods</h4>Herein, we performed comprehensive molecular characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequenci ...[more]

PMID: 34986867

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Project description:ObjectiveTo investigate the predictive value of radiomics models based on intra-tumoral ecological diversity (iTED) and temporal characteristics for assessing microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC).Material and methodsWe retrospectively analyzed the data of 398 HCC patients who underwent dynamic contrast-enhanced MRI with Gd-EOB-DTPA (training set: 318; testing set: 80). The tumors were segmented into five distinct habitats using case-level clustering and a Gaussian mixture model was used to determine the optimal clusters based on the Bayesian information criterion to produce an iTED feature vector for each patient, which was used to assess intra-tumoral heterogeneity. Radiomics models were developed using iTED features from the arterial phase (AP), portal venous phase (PVP), and hepatobiliary phase (HBP), referred to as MiTED-AP, MiTED-PVP, and MiTED-HBP, respectively. Additionally, temporal features were derived by subtracting the PVP features from the AP features, creating a delta-radiomics model (MDelta). Conventional radiomics features were also extracted from the AP, PVP, and HBP images, resulting in three models: MCVT-AP, MCVT-PVP, and MCVT-HBP. A clinical-radiological model (CR model) was constructed, and two fusion models were generated by combining the radiomics or/and CR models using a stacking algorithm (fusion_R and fusion_CR). Model performance was evaluated using AUC, accuracy, sensitivity, and specificity.ResultsThe MDelta model demonstrated higher sensitivity compared to the MCVT-AP and MCVT-PVP models. No significant differences in performance were observed across different imaging phases for either conventional radiomics (p = 0.096-0.420) or iTED features (p = 0.106-0.744). Similarly, for images from the same phase, we found no significant differences between the performance of conventional radiomics and iTED features (AP: p = 0.158; PVP: p = 0.844; HBP: p = 0.157). The fusion_R and fusion_CR models enhanced MVI discrimination, achieving AUCs of 0.823 (95% CI: 0.816-0.831) and 0.830 (95% CI: 0.824-0.835), respectively.ConclusionDelta radiomics features are temporal and predictive of MVI, providing additional predictive information for MVI beyond conventional AP and PVP features. The iTED features provide an alternative perspective in interpreting tumor characteristics and hold the potential to replace conventional radiomics features to some extent for MVI prediction.

Dataset Information

Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial.

Background

Methods

Results

Conclusions

Trial registration

Publications

Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial.

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