Abstract 174P
Background
Hepatocellular carcinoma (HCC) remains one of the most difficult cancers to treat effectively, despite rapid advancements in immunotherapy. The overall prognosis for HCC patients continues to be unsatisfactory. Glypican-3 (GPC3) specific chimeric antigen receptor T (CAR-T) cell therapy has shown promise. However, patient responses have been highly variable, with many patients not experiencing significant therapeutic benefits. One significant challenge is the limited infiltration of CAR-T cells into the tumour microenvironment, which hampers therapeutic efficacy. Locoregional administration of GPC3 CAR-T cells, which involves delivering the cells directly to the liver, has been proposed as a strategy to enhance tumour infiltration and improve clinical outcomes.
Methods
This study aimed to investigate the therapeutic efficacy and mechanisms underlying locoregional GPC3 CAR-T cell delivery in HCC. Using orthotopic mouse HCC xenograft models, CAR-T cells were administered either locoregionally via the portal vein or systemically via the tail vein. The effects of these delivery methods on tumour growth, liver function, and CAR-T cell infiltration were compared.
Results
Locoregional administration of CAR-T cells significantly outperformed systemic delivery in controlling tumour growth and improving liver function. The locoregional delivery group exhibited a higher percentage of tumour-infiltrating CAR-T cells, which demonstrated enhanced cytotoxicity, better chemotaxis, and reduced exhaustion. Additionally, in a metastatic model with both orthotopic and extrahepatic tumours, portal vein injection showed superior tumour inhibition compared to tail vein injection.
Conclusions
This study demonstrated that locoregional administration of CAR-T cells leads to increased tumour infiltration and enhanced therapeutic efficacy in HCC. The findings suggest that locoregional CAR-T therapy could be particularly beneficial for late-stage patients with distant metastases, offering a promising strategy to improve outcomes in this challenging patient population.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The Chinese University of Hong Kong.
Funding
Research Grants Council of Hong Kong; The Children’s Cancer Foundation of Hong Kong; Innovation Technology Commission of the Hong Kong SAR, China.
Disclosure
All authors have declared no conflicts of interest.