Novel Cellular Therapies for Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Most patients present with advanced disease, and current gold-standard management using tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs) offers modest clinical benefit. Cellular immune therapies targeting HCC are currently being tested in the laboratory and in clinical trials. Here, we review the landscape of cellular immunotherapy for HCC, defining antigenic targets, outlining the range of cell therapy products being applied in HCC (such as CAR-T and TCR-T), and exploring how advanced engineering solutions may further enhance this therapeutic approach.

Keywords: chimeric antigen receptor (CAR) T-cells; engineered TCR T-cells; hepatocellular carcinoma; immunotherapy.

Figure 1

Immune-based and TKI therapies for HCC. Approved drugs and investigational agents are listed, including checkpoint inhibitors (ICIs), adoptive T cell therapies, small molecule inhibitors of angiogenesis and tumour growth, monoclonal antibodies targeting angiogenesis and oncolytic viruses and vaccines.

Figure 2

Structure of T-cell receptors (TCR) and Chimeric antigen receptors (CAR-T). (a) CAR-T cells recognise tumour antigens in an MHC-unrestricted manner. Target binding induces T cell activation, proliferation and cytotoxicity. (b) CAR-T design has evolved over time. 1st generation CARs comprise an extracellular scFv recognising a specific antigen connected to a transmembrane domain via a hinge with a CD3ζ endodomain. 2nd generation CARs include an additional costimulatory moeity such as CD28, whereas 3rd generation CARs have two co-stimulatory domains linked to the CD3ζ chain, e.g., 41BB and CD28, with the aim of improving CAR-T functionality and persistence. 4th generation CARs, ‘armoured CARs’, incorporate modules for cytokine production, e.g., IL-12, with the aim of improving CAR-T proliferation and persistence whilst concurrently stimulating endogenous immune compartments within the tumour microenvironment. (c) The T cell receptor (TCR) complex comprises engineered α and β chains in association with CD3 chains. Engineered TCRs interact with major histocompatibility complex (MHC)-antigen peptide complexes on cancer cells, to induce T cell activation and to promote tumour eradication.

Figure 3

Solid tumour CAR T-cell challenges and potential strategies to overcome these. There are many obstacles to the design and delivery of effective CAR T-cell therapy for solid tumours. This includes physical barriers to tumour infiltration, heterogeneity of antigen expression, immunosuppressive factors in the tumour microenvironment and potentially challenging clinical toxicities. There are several novel engineering solutions to address each of these issues, as outlined in this figure. Key: BiTEs, bi-specific T cell engagers; CRS, cytokine release syndrome; CTLA-4, cytotoxic T lymphocyte protein 4; ICANS, immune effector cell-associated neurotoxicity syndrome; MDSCs, myeloid-derived suppressor cells; PD-1, programmed cell death 1; PD-L1, programmed cell death 1 ligand 1; scFv, single-chain Ig variable fragment; TGFβ, transforming growth factor-β; Treg, regulatory T cells.