Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma

Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma

Journal for ImmunoTherapy of Cancer

10.1136/jitc-2023-007106

http://dx.doi.org/10.1136/jitc-2023-007106

Neslihan Arife Kaya, David Tai, Xinru Lim, Jia Qi Lim, Mai Chan Lau, Denise Goh, Cheryl Zi Jin Phua, Felicia Yu Ting Wee, Craig Ryan Joseph, Jeffrey Chun Tatt Lim, Zhen Wei Neo, Jiangfeng Ye, Lawrence Cheung, Joycelyn Lee, Kelvin S H Loke, Apoorva Gogna, Fei Yao, May Yin Lee, Timothy Wai Ho Shuen, Han Chong Toh, Axel Hilmer, Yun Shen Chan, Tony Kiat-Hon Lim, Wai Leong Tam, Su Pin Choo, Joe Yeong, Weiwei Zhai

16 August 2023

Kaya, N. A., Tai, D., Lim, X., Lim, J. Q., Lau, M. C., Goh, D., Phua, C. Z. J., Wee, F. Y. T., Joseph, C. R., Lim, J. C. T., Neo, Z. W., Ye, J., Cheung, L., Lee, J., Loke, K. S. H., Gogna, A., Yao, F., Lee, M. Y., Shuen, T. W. H., … Zhai, W. (2023). Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma. Journal for ImmunoTherapy of Cancer, 11(8), e007106. https://doi.org/10.1136/jitc-2023-007106

BackgroundCombination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown.MethodsBy collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial.ResultsWe found that higher tumor mutation burden,NCOR1mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9+/CXCR3+macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy.ConclusionsThis study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC.

Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

This research / project is supported by the National Medical Research Council - Clinician Scientist Individual Research Grant
Grant Reference no. : NMRC/CIRG/1454/2016

This research / project is supported by the Singapore National Medical Research Council - Translational and Clinical Research Flagship Programme
Grant Reference no. : TCR/015-NCC/2016

This research / project is supported by the National Medical Research Council - NA
Grant Reference no. : MOH-000323-00

This research / project is supported by the National Medical Research Council - Open Fund - Young Individual Research Grant
Grant Reference no. : OFYIRG19may-0007

This research / project is supported by the National Medical Research Council - Open Fund Large Collaborative Grant
Grant Reference no. : NMRC/OFLCG/003/2018

This research / project is supported by the A*STAR Biomedical Research Council - IAF-PP grant (HBMS)
Grant Reference no. : H19/01/a0/024

This research/project is supported by the National Natural Science Foundation of China (32293190/32293192, 31970566), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB17), National Key R&D Program of China (2018YFC1406902)

https://oar.a-star.edu.sg/communities-collections/articles/20674

2051-1426

Bioinformatics Institute