Exploring Glypican-3 Targeted CAR-NK Treatment and Potential Therapy
Resistance in Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most prevalent form of primary
liver cancer and ranks as the second leading cause of cancer-related
mortality globally. Despite advances in current HCC treatment, it
remains a malignancy with poor prognosis. Therefore, developing novel
treatment options for patients with HCC is urgently needed. Chimeric
antigen receptor (CAR)-modified natural killer (NK) cells have shown
potent anti-tumor effects, making them as a promising immunotherapy
strategy for cancer treatment. Glypican-3 (GPC3), a cell surface
oncofetal glycoprotein, is highly expressed in most HCC tissues, but not
in normal tissues, and functions as a key driver of carcinogenesis.
Given its high expression level on the cell surface, GPC3 is considered
as an attractive immunotherapy target for HCC. In this study, two
GPC3-specific CAR-NK cells, NK92MI/NH3 and NK92MI/HS20, were established
using NK92MI cells, a modified IL-2-independent NK cell line. These cell
lines were engineered with third generation GPC3-specific CAR, and their
activities were subsequently evaluated in the treatment of HCC. We found
that NK92MI/NH3 cells, rather than NK92MI/HS20 cells, exhibited a
significant cytotoxicity effect against GPC3 + HepG2
cells in vitro and efficiently suppressed tumor growth in a xenograft
model using NSG mice. In addition, irradiated NK92MI/NH3 cells displayed
similar anti-tumor efficacy to unirradiated NK92MI/NH3 cells.
Furthermore, we observed that NK92MI/NH3 cells showed higher killing
activity against the GPC3 isoform 2 overexpression cell line
(SK-Hep1-v2) than those with GPC3 isoform 1 overexpression cell line
(SK-Hep1-v1) both in vitro and in vivo. This suggest that the presence
of different GPC3 isoforms in HCC may impact the cytotoxicity activity
of NK92MI/NH3 cells and potentially influence therapeutic outcomes.
These findings highlight the effective anti-HCC effects of NK92MI/HN3
cells, as well as the underlying therapy resistance, suggesting their
potential as a promising therapy for HCC.