@article{8d72b3ec82d34e7494b4655ea43c91a6,
title = "Integrated immunological analysis of a successful conversion of locally advanced hepatocellular carcinoma to resectability with neoadjuvant therapy",
abstract = "Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide with a minority of patients being diagnosed early enough for curative-intent interventions. We report the first use of preoperative cabozantinib plus nivolumab to successfully downstage what presented as unresectable HCC as part of an ongoing phase 1b study. Preoperative treatment with cabozantinib and nivolumab led to >99% reduction in alpha-fetoprotein,-37.3% radiographic reduction by RECIST 1.1 and a near complete pathologic response (80% to 100% necrosis). An integrated immunological analysis was performed on the post-treatment surgical tumor sample and matched pre-treatment and post-treatment peripheral blood samples with high-dimensional imaging and cytometry techniques. Bayesian non-negative matrix factorization (CoGAPS, Coordinated Gene Activity in Pattern Sets) and self-organizing map (FlowSOM) algorithms were used to distinguish changes in functional markers across cellular neighborhoods in the single cell data sets. Brisk immunological infiltration into the tumor microenvironment was observed in non-random, organized cellular neighborhoods. Systemically, combination therapy led to marked promotion of effector cytotoxic T cells and effector memory helper T cells. Natural killer cells also increased with therapy. The patient remains without disease recurrence and with a normal alpha-fetoprotein approximately 2 years from presentation. Our study provides proof-of-concept that borderline resectable or locally advanced HCC warrants consideration of downstaging with effective neoadjuvant systemic therapy for subsequent curative resection. ",
keywords = "combination, computational biology, drug therapy, gastrointestinal neoplasms, immunotherapy, tumor microenvironment",
author = "Ho, {Won Jin} and Gaurav Sharma and Qingfeng Zhu and Genevieve Stein-O'brien and Jennifer Durham and Robert Anders and Aleksandra Popovic and Guanglan Mo and Ihab Kamel and Weiss, {Matthew J} and Elizabeth Jaffee and Fertig, {Elana J.} and Mark Yarchoan",
note = "Funding Information: Funding Funding for this clinical trial were provided by Exelixis and Bristol Myers Squibb (to MY). Additional research support was provided by the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924), the NIH Center Core Grant (P30 CA006973), and the Emerson Collective Cancer Research Fund (640183). Funding Information: Competing interests WH is a co-inventor of patents with potential for receiving royalties from Rodeo Therapeutics unrelated to the current study. MY reports receiving a commercial research grant from Bristol Myers Squibb, Exelixis, and Merck & Co and is a consultant/advisory board member for Eisai and Exelixis. EJF is a consultant for Champions Oncology. EMJ reports receiving a commercial research grant from Bristol Myers Squibb, Aduro Biotech, and Amgen, has ownership interest (including stock, patents, and so on) in Aduro Biotech, and is a consultant/advisory board member for CStone, Dragonfly, Genocea, and Adaptive Biotechnologies. Funding Information: Funding for this clinical trial were provided by Exelixis and Bristol Myers Squibb (to MY). Additional research support was provided by the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924), the NIH Center Core Grant (P30 CA006973), and the Emerson Collective Cancer Research Fund (640183). Publisher Copyright: {\textcopyright} 2020 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
year = "2020",
month = nov,
day = "20",
doi = "10.1136/jitc-2020-000932",
language = "English (US)",
volume = "8",
journal = "Journal for ImmunoTherapy of Cancer",
issn = "2051-1426",
publisher = "BioMed Central",
number = "2",
}