TY - JOUR
T1 - Neoadjuvant cabozantinib and nivolumab convert locally advanced hepatocellular carcinoma into resectable disease with enhanced antitumor immunity
AU - Ho, Won Jin
AU - Zhu, Qingfeng
AU - Durham, Jennifer
AU - Popovic, Aleksandra
AU - Xavier, Stephanie
AU - Leatherman, James
AU - Mohan, Aditya
AU - Mo, Guanglan
AU - Zhang, Shu
AU - Gross, Nicole
AU - Charmsaz, Soren
AU - Lin, Dongxia
AU - Quong, Derek
AU - Wilt, Brad
AU - Kamel, Ihab R.
AU - Weiss, Matthew
AU - Philosophe, Benjamin
AU - Burkhart, Richard
AU - Burns, William R.
AU - Shubert, Chris
AU - Ejaz, Aslam
AU - He, Jin
AU - Deshpande, Atul
AU - Danilova, Ludmila
AU - Stein-O’Brien, Genevieve
AU - Sugar, Elizabeth A.
AU - Laheru, Daniel A.
AU - Anders, Robert A.
AU - Fertig, Elana J.
AU - Jaffee, Elizabeth M.
AU - Yarchoan, Mark
N1 - Funding Information:
We thank the patients and their families who participated in this research and the clinical and laboratory research teams. We also thank E. Wang, A. Cooper and S. Isibor for helpful discussions and technical assistance. We thank the University of Maryland School of Medicine Center for Innovative Biomedical Resources Flow Cytometry and Mass Cytometry Core Facility for their help with the CyTOF data collection and acknowledge the support of Therapeutics Insights Services at Fluidigm for the IMC data collection. Finally, we acknowledge the support from the Emerson Collective Cancer Research Fund (grant no. 640183 to E.M.J.), the National Cancer Institute (NCI) Specialized Program of Research Excellence in Gastrointestinal Cancers (grant no. P50CA062924 to E.M.J.), the NCI Informatics Technologies for Cancer Research (grant no. U01CA212007 to E.J.F.), the National Institutes of Health (NIH) Multiscale Modeling Consortium (grant no. U01CA212007 to E.J.F.), Exelixis (M.Y.), Bristol Myers Squibb (M.Y.), the NIH Center Core Grant P30CA006973 and Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy.
Funding Information:
W.J.H. is a coinventor of patents with potential for receiving royalties from Rodeo Therapeutics, is a consultant for Exelixis and receives research funding from Sanofi. R.A.A. reports receiving a commercial research support from Bristol Myers Squibb and is a consultant/advisory board member for Bristol Myers Squibb, Merck, AstraZeneca, Incyte and RAPT Therapeutics. E.M.J. reports receiving a commercial research grant from Bristol Myers Squibb and Aduro Biotech and is a consultant/advisory board member for the Lustgarten Foundation, Parker Institute for Cancer Immunotherapy, CStone Pharmaceuticals, Dragonfly, Genocea, Achilles Therapeutics and Adaptive Biotechnologies; she is cofounder of Abmeta Biotech. M.Y. reports receiving research grants from Incyte, Bristol Myers Squibb and Exelixis and is a consultant for AstraZeneca, Eisai, Exelixis and Genentech. The other authors declare no competing interests.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/9
Y1 - 2021/9
N2 - A potentially curative hepatic resection is the optimal treatment for hepatocellular carcinoma (HCC) but most patients are not candidates for resection and most resected HCCs eventually recur. Until recently, neoadjuvant systemic therapy for HCC has been limited by a lack of effective systemic agents. Here, in a single-arm phase 1b study, we evaluated the feasibility of neoadjuvant cabozantinib and nivolumab in patients with HCC, including patients outside of traditional resection criteria (ClinicalTrials.gov ID NCT03299946). Of 15 patients enrolled, 12 (80%) underwent successful margin-negative resection and 5 out of 12 (42%) had major pathological responses. In-depth biospecimen profiling demonstrated an enrichment in effector T cells, as well as tertiary lymphoid structures, CD138+ plasma cells, and a distinct spatial arrangement of B cells in responders compared to nonresponders, indicating an orchestrated B cell contribution to antitumor immunity in HCC.
AB - A potentially curative hepatic resection is the optimal treatment for hepatocellular carcinoma (HCC) but most patients are not candidates for resection and most resected HCCs eventually recur. Until recently, neoadjuvant systemic therapy for HCC has been limited by a lack of effective systemic agents. Here, in a single-arm phase 1b study, we evaluated the feasibility of neoadjuvant cabozantinib and nivolumab in patients with HCC, including patients outside of traditional resection criteria (ClinicalTrials.gov ID NCT03299946). Of 15 patients enrolled, 12 (80%) underwent successful margin-negative resection and 5 out of 12 (42%) had major pathological responses. In-depth biospecimen profiling demonstrated an enrichment in effector T cells, as well as tertiary lymphoid structures, CD138+ plasma cells, and a distinct spatial arrangement of B cells in responders compared to nonresponders, indicating an orchestrated B cell contribution to antitumor immunity in HCC.
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U2 - 10.1038/s43018-021-00234-4
DO - 10.1038/s43018-021-00234-4
M3 - Article
C2 - 34796337
AN - SCOPUS:85111622429
SN - 2662-1347
VL - 2
SP - 891
EP - 903
JO - Nature Cancer
JF - Nature Cancer
IS - 9
ER -