CAR T Cells Improve Antitumor Activity in Hepatocellular Carcinoma

November 1, 2018

Gene-edited glypican-3 (GPC3)-targeted chimeric antigen receptor (CAR) T cells with deficient programmed death–1 have greater cytotoxicity compared with wild-type GPC3-targeted T cells in GPC3-positive hepatocellular carcinoma, based on results from a recent study.

Gene-edited glypican-3 (GPC3)-targeted chimeric antigen receptor (CAR) T cells with deficient programmed death 1 (PD-1) have greater cytotoxicity compared with wild-type GPC3-targeted T cells in GPC3-positive hepatocellular carcinoma (HCC), based on results from a recent study.

HCC is one of the leading causes of cancer-related deaths. By the time most patients receive a diagnosis of HCC, many curative treatments such as ablation, surgery, and chemotherapy are not as effective. CAR T cells are a newly engineered immunotherapy that has shown response in leukemia and lymphoma, or nonsolid cancers. In solid tumors, the efficacy of CAR T cells has been somewhat diminished due to the immunosuppressive tumor microenvironment that exists and impairs the function of adoptively transferred T cells.

One of the examples of the tumor microenvironment that suppresses T-cell activation is the expression of PD-1 on tumor cells. In the study by Guo et al, the gene expressing the PD-1 receptor on CAR T cells was disrupted to test if it provides better effectiveness against PD-L1 expressing HCC than wild-type CAR T cells.

In this study, second-generation GPC3-targeted CAR T cells, using the CRISPR-Cas9 gene-editing system, were modified to be deficient in PD-1. These CAR T cells were then compared with wild-type CAR T cells. When comparing them, investigators found that the GPC3 CAR T cells with PD-1 deficiency had significantly stronger tumor lysis activity than wild-type GPC3 CAR T cells on GPC3-positive HCC cells. However, the efficacy was limited in both cell types when treating GPC3-negative HCC cells, indicating that PD-1 deficiency did not help to treat these type of cancer cells.

The study further found that there were also significantly increased Akt activation and greater expression of antiapoptotic protein Bcl-xL in the PD-1—deficient CAR T cells. These results coincide with a stronger antitumor activity in this cell type compared with wild-type CAR T cells. Tumor volumes and tumor weights of mice treated with PD-1–deficient GPC3 CAR T cells were significantly smaller than wild-type CAR T cells. In addition, tumor-related gene expressions were significantly inhibited to a larger degree in PD-1–deficient CAR T cells compared with wild-type CAR T cells. Lastly, when the peripheral blood of the mice was tested, the density of PD-1–deficient CAR T cells was significantly higher than that of wild-type CAR T cells at 20 days post infusion, proving greater in vivo survival for PD-1–deficient CAR T cells.

HCC is a cancer that is usually diagnosed in later stages, leading to limited high-efficacy treatment regimens being available. Immunotherapy, in particular, CAR T cells, have greatly improved the treatment of many types of cancers. In this study, investigators found that gene-edited CAR T cells with PD-1 deficiency have stronger antitumor activity than wild-type CAR T cells. Future development of CAR T cells with modified gene editing may help improve CAR T cell efficacy and help treat solid tumors, such as HCC.

Reference

Guo X, Jiang H, Shi B, et al. Disruption of PD-1 enhanced the anti-tumor activity of chimeric antigen receptor T cells against hepatocellular carcinoma. Front Pharmacol. 2018;9:1118. doi: 10.3389/fphar.2018.01118.