Hepatocellular carcinoma (HCC) is a primary type of liver cancer that ranks as the fourth most leading cause of cancer-related deaths world-wide. Treatment options including ablation and chemotherapies are not always efficient to eliminate advanced HCC. Immunotherapies have general low response rates in advanced HCC patients, indicating that new approaches are needed in order to improve the current clinical responses. Our main objective is to identify mutations that can be clinically relevant targets for T cell immunotherapy in HCC patients.
Here we present data from three advanced HCC patients that underwent liver transplantation. Tumors from the explanted livers were sequenced with the Illumina Trusight Oncology 500 platform. This platform allowed us to focus on clinically relevant tumor mutations and at the same time acquire information on the patient HLA restriction, in order to perform HLA binding prediction analysis. The mutations were ranked according to their specific relevance for HCC, presence of frequent substitutions (hot-spot) and likelihood of HLA binding. The screening of the synthesized peptides and minigenes encoding the top-ranking mutations for their ability to activate T cells is ongoing.
16, 13 and 7 top ranking somatic mutations were identified respectively for the three patients. Among those, we identified ‘hot-spot’ mutations in driver oncogenes such as the CTNNB1 and other highly frequent HCC associated genes including the PIK3CA, CDKN2A and KMT2C. For each frequent HLA allele such as A*01, A*02, A*03, B*07 and C*03 we identified between 4 and 12 peptides with high predicted binding affinity.
Based on these preliminary data from three advanced HCC samples, we identified hot-spot mutations in driver oncogenes and highly frequent HCC associated genes. We also identified potential high affinity binders for frequently expressed HLA class I alleles. These data are increasing the likelihood of identifying T cell receptors that can be used for T cell-based immunotherapy broadly in a high number of cancer patients. The immunological testing of these mutations and the identification of specific T cell receptors is still ongoing.
Legal entity responsible for the study
Center for Innovative Medicine and Sjöberg Foundation.
All authors have declared no conflicts of interest.