Engineering T cells for immunotherapy of primary human hepatocellular carcinoma

Abstract

Liver cancers, majority of which are primary hepatocellular carcinoma (HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4 th most common cause of male cancer deaths. Novel therapies are urgently needed. Over last few years, immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells, have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific T cells genetically engineered with the T cell receptor genes (TCRTs) and the chimeric antigen receptor genes (CARTs). We first review the current options of TCRTs and CARTs immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of TCRTs and CARTs to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better TCRTs and CARTs to achieve more effective and durable antitumor effects.

Early diagnosis and therapeutic strategies for hepatocellular carcinoma: From bench to bedside

“…, cluster of differentiation 28 [CD28], 4-1BB, and CD134). Then the activated T cells rapidly perform immune functions to kill targeted cells[ 93 - 95 ]. Unrestricted by major histocompatibility complex (MHC), CAR-T cells can directly recognize tumor cells and avoid the immune-evasion mechanism of tumor cells via down-regulation of MHC[ 96 ].…”

“…Several HCC-related antigens targeted by TCR have been identified, e.g. , AFP-, GPC3-, virus-, NY-ESO-1-, and hTERT-specific TCRs[ 95 ]. Despite the success of NY-ESO-1-targeted TCR-T cells to treat multiple myeloma and synovial sarcoma, recent studies about TCR-T for HCC focus on targeting AFP[ 95 ].…”

“…, AFP-, GPC3-, virus-, NY-ESO-1-, and hTERT-specific TCRs[ 95 ]. Despite the success of NY-ESO-1-targeted TCR-T cells to treat multiple myeloma and synovial sarcoma, recent studies about TCR-T for HCC focus on targeting AFP[ 95 ]. The generation of affinity-optimized TCRs with specificity to AFP-positive tumors calls for the identification of novel AFP peptides; for example, the construction of HLA-A2/AFP 158 -specific TCRs and HLA-A24/AFP 2-11 -specific TCR forms the foundation to develop effective and safe TCR-T cells-based immunotherapies[ 103 - 105 ].…”

APDL1-CART cells exhibit strong PD-L1-specific activity against leukemia cells

“…Previous studies have shown that engineered T cells engrafted with antigen-specific receptors may induce major histocompatibility complex (MHC)-independent immune responses that efficiently enhance anti-tumor immunity and cytokine production [ 5 – 7 ]. Chimeric antigen receptors (CARs) are constructed by linking the variable regions of the heavy and light chains of an antibody specific for a tumor cell surface molecule to the intracellular activation domain of the T-cell receptor.…”

Identification of Driver Genes Regulating the T-Cell–Infiltrating Levels in Hepatocellular Carcinoma

“…Clinically, limited early symptoms in HCC patients could lead to delayed diagnoses, which greatly undermines the survival outcomes of HCC patients ( Sun et al, 2020 ). For patients with advanced stage HCC, whose conditions are usually not suitable for surgical resection, immunotherapies are considered as an effective and promising strategy ( Caraballo Galva et al, 2020 ).…”