Preclinical evidence using an genetically engineered mouse model of IDH1-mutated intrahepatic CCA indicates that the selective IDH1 inhibitor ivosidenib mediates its antitumor activity by promoting hepatic progenitor-cell differentiation, and inducing T-cell–mediated antitumor immune response.
Among the most common genetic alterations in intrahepatic CCA are mutations in the isocitrate dehydrogenase (IDH)1 and IDH2 enzymes. These mutations are present in approximately 20% of patients. IDH proteins are enzymes involved in diverse cellular processes, including histone demethylation and DNA modification. A critical component of the tricarboxylic acid (ie, citric acid or Krebs) cycle is the IDH2 protein, which is localized in the mitochondria.
The mutated IDH protein exhibits aberrant enzymatic function, reducing alpha-ketoglutarate (αKG, which plays a critical role in the metabolism of cellular energy) to the oncometabolite 2-hydroxyglutarate (2-HG). The 2-HG competitively inhibits αKG-dependent histone and DNA demethylating enzymes, thereby altering the regulation of chromatin, which plays a crucial role in regulating gene expression.
In phase 1 and 2 clinical trials of patients with intrahepatic CCA and IDH1 mutation, the first-in-class small-molecule ivosidenib (Tibsovo), a selective IDH1 inhibitor, has shown benefit. Data from the 2 clinical trials were so convincing that the National Comprehensive Cancer Network (NCCN) added ivosidenib to its updated guidelines of hepatobiliary cancers published on June 1, 2020.
According to the NCCN Drugs & Biologics Compendium specific recommendation, the drug is approved for “Subsequent treatment as a single-agent…for progression on or after systemic treatment for unresectable or metastatic disease with an isocitrate dehydrogenase-1 (IDH1) mutation.”
Meng-Ju Wu, PhD, MS, Postdoctoral Research Fellow, Center for Cancer Research, Massachusetts General Hospital, Boston, and colleagues explored the relationship between treatment with ivosidenib and the vehicle therapy, and the mechanism underlying the response to the inhibition of IDH1, using a proprietary, first genetically engineered mouse model of intrahepatic CCA with IDH1 mutation. Results were presented by Dr Wu at an oral presentation during this year’s annual meeting of the American Association for Cancer Research (AACR).
Along with reducing the overall tumor burden—a reduction of tumor-produced 2-HG >85% was also observed—ivosidenib was discovered to promote hepatocyte-cell differentiation (2-HG hinders hepatic progenitor-cell differentiation) to mature hepatocytes.
In addition, Dr Wu and colleagues detected an enhanced immune response to ivosidenib in this mouse model. They noted an increased recruitment of CD8-positive T-cells to the tumors. This increase is important because the tumor microenvironment in intrahepatic CCA dampens the activity of CD8-positive T-cells and other immune cells, such as natural killer cells and dendritic cells. Pronounced induction of immune stimulatory interferon signaling was noted, and PD-L1 expression was upregulated.
Dr Wu concluded at the AACR meeting, “My study provides the first faithful genetically engineered mouse model of IDH1-mutated intrahepatic cholangiocarcinoma. It will elucidate the tumor maintenance program driven by IDH1 mutation, defining the impact of this oncogene on tumor-cell epigenetic programs and tumor-immune microenvironment interplay. The work provides a strong preclinical rationale for combination treatment strategies involving ivosidenib in patients with intrahepatic cholangiocarcinoma and IDH1 mutation.”
Source: Wu MJ, et al. Cancer Res. 2020;80(16_suppl). Abstract 1810.