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

Liang Dong, Zhi Cao, Meixia Chen, Yang Liu, Xinran Ma, Yuting Lu, Yan Zhang, Kaichao Feng, Yang Zhang, Zhenzhen Meng, Qingming Yang, Yao Wang (), Zhiqiang Wu () and Weidong Han ()
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Liang Dong: Chinese PLA General Hospital
Zhi Cao: Chinese PLA General Hospital
Meixia Chen: Chinese PLA General Hospital
Yang Liu: Chinese PLA General Hospital
Xinran Ma: Chinese PLA General Hospital
Yuting Lu: Chinese PLA General Hospital
Yan Zhang: Chinese PLA General Hospital
Kaichao Feng: Chinese PLA General Hospital
Yang Zhang: Chinese PLA General Hospital
Zhenzhen Meng: Chinese PLA General Hospital
Qingming Yang: Chinese PLA General Hospital
Yao Wang: Chinese PLA General Hospital
Zhiqiang Wu: Chinese PLA General Hospital
Weidong Han: Chinese PLA General Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51495-3

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