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Inhibition of glycosphingolipid synthesis with eliglustat in combination with immune checkpoint inhibitors in advanced cancers: preclinical evidence and phase I clinical trial.

ABSTRACT: Glycosphingolipids (GSLs) are abundantly expressed in cancer cells. The effects of GSL-targeted immunotherapies are not fully understood. Here, we show that the inhibition of GSL synthesis with the UDP-glucose ceramide glucosyltransferase inhibitor eliglustat can increase the exposure of the major histocompatibility complex (MHC) and tumour antigen peptides, enhancing the antitumour response of CD8⁺ T cells in a range of tumour models. We therefore conducted a proof-of-concept phase I trial on the combination of eliglustat and an anti-PD-1 antibody for the treatment of advanced cancers (NCT04944888). The primary endpoints were safety and feasibility, and the secondary endpoint was antitumor activity. All prespecified endpoints were met. Among the 31 enrolled patients, only 1 patient experienced a grade 3 adverse event (AE), and no grade 4 AEs were observed. The objective response rate was 22.6% and the disease control rate reached 71%. Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease. In summary, inhibiting the synthesis of GSLs might represent an effective immunotherapy approach.

SUBMITTER: Dong L

PROVIDER: S-EPMC11322526 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Inhibition of glycosphingolipid synthesis with eliglustat in combination with immune checkpoint inhibitors in advanced cancers: preclinical evidence and phase I clinical trial.

Dong Liang L Cao Zhi Z Chen Meixia M Liu Yang Y Ma Xinran X Lu Yuting Y Zhang Yan Y Feng Kaichao K Zhang Yang Y Meng Zhenzhen Z Yang Qingming Q Wang Yao Y Wu Zhiqiang Z Han Weidong W

Nature communications 20240814 1

Glycosphingolipids (GSLs) are abundantly expressed in cancer cells. The effects of GSL-targeted immunotherapies are not fully understood. Here, we show that the inhibition of GSL synthesis with the UDP-glucose ceramide glucosyltransferase inhibitor eliglustat can increase the exposure of the major histocompatibility complex (MHC) and tumour antigen peptides, enhancing the antitumour response of CD8<sup>+</sup> T cells in a range of tumour models. We therefore conducted a proof-of-concept phase I ...[more]

PMID: 39138212

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Project description:ImportanceAlthough immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs.ObjectiveTo assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors.Design, setting, and participantsThis open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023.InterventionsPatients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions).Main outcomes and measuresThe primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population.ResultsAmong 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred.Conclusions and relevanceThis phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS.Trial registrationClinicalTrials.gov Identifier: NCT03511391.

Project description:ImportanceCheckpoint inhibitors have a unique mechanism of action that differs from chemotherapy or targeted therapies. The validity of objective response rate (ORR) as a surrogate for progression-free survival (PFS) and overall survival (OS) in checkpoint-inhibitor trials is uncertain.ObjectiveTo determine the types of primary end points used in phase 2 checkpoint-inhibitor trials, and to assess the strength of associations for ORR with PFS and OS.Data sourcesTrials listed in electronic databases from 2000 to 2017 (PREMEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials).Study selectionAdvanced solid cancers in phase 2 and phase 3 trials.Data extraction and synthesisCorrelations between ORR odds ratios and hazard ratios (HRs) for PFS and OS were examined for randomized comparisons. Within checkpoint-inhibitor treatment arms, correlations for ORR with 6-month PFS and 12-month OS rates were examined. All analyses were weighted by trial size. Multivariable models to predict 6-month PFS and 12-month OS rates from ORR were developed and their performance validated in an independent sample of trials.Main outcomes and measuresCorrelation coefficient (r) of ORR with PFS and OS.ResultsOf 87 phase 2 trials identified, ORR was the most common (52 [60%]) primary end point. Twenty randomized clinical trials with 25 treatment comparisons were identified. Checkpoint-inhibitor therapy was associated with pooled ORR of 24% (95% CI, 18%-31%). For randomized comparisons, r between ORR odds ratio and PFS HR was 0.63 (95% CI, 0.35-0.89), ORR odds ratio and OS HR was 0.57 (95% CI, 0.23-0.89), and between PFS HR and OS HR was 0.42 (95% CI, 0.04-0.81). Within the checkpoint-inhibitor arms, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% CI, -0.06 to 0.95), 0.08 (95% CI, -0.17 to 0.70), and 0.74 (95% CI, 0.57-0.92), respectively. In validation, when 6-month PFS was used to predict 12-month OS, there was a good calibration between actual and predicted 12-month OS. When ORR was used to predict 6-month PFS and 12-month OS rates, respectively, the actual vs predicted rates calibrated poorly.Conclusions and relevanceIn checkpoint-inhibitor trials, ORR correlated poorly with OS. For future phase 2 studies, 6-month PFS rate is recommended as an end point.

Dataset Information

Inhibition of glycosphingolipid synthesis with eliglustat in combination with immune checkpoint inhibitors in advanced cancers: preclinical evidence and phase I clinical trial.

Publications

Inhibition of glycosphingolipid synthesis with eliglustat in combination with immune checkpoint inhibitors in advanced cancers: preclinical evidence and phase I clinical trial.

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