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Published on: April 6, 2015
Development of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technology
Keming Lin1, Baijin Xia1, Xuemei Wang1
1Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou, Guangdong, 510080, People's Republic of China.
Background:
Chimeric antigen receptor T (CAR-T) cell therapy, as an emerging anti-tumor treatment, has garnered extensive attention in the study of targeted therapy of multiple tumor-associated antigens in hepatocellular carcinoma (HCC). However, the suppressive microenvironment and individual heterogeneity results in downregulation of these antigens in certain patients' cancer cells. Therefore, optimizing CAR-T cell therapy for HCC is imperative.
Methods:
In this study, we administered FGFR4-ferritin (FGFR4-HPF) nanoparticles to the alpaca and constructed a phage library of nanobodies (Nbs) derived from alpaca, following which we screened for Nbs targeting FGFR4. Then, we conducted the functional validation of Nbs. Furthermore, we developed Nb-derived CAR-T cells and evaluated their anti-tumor ability against HCC through in vitro and in vivo validation.
Results:
Our findings demonstrated that we successfully obtained high specificity and high affinity Nbs targeting FGFR4 after screening. And the specificity of Nbs targeting FGFR4 was markedly superior to their binding to other members of the FGFR family proteins. Furthermore, the Nb-derived CAR-T cells, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in both experiments when in vitro and in vivo.
Conclusions:
In summary, the results of this study suggest that the CAR-T cells derived from high specificity and high affinity Nbs, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in vitro and in vivo. This is an exploration of FGFR4 in the field of Nb-derived CAR-T cell therapy for HCC, holding promise for enhancing safety and effectiveness in the clinical treatment of HCC in the future.
Insights
This study developed novel nanobody-derived CAR-T cells targeting FGFR4 for hepatocellular carcinoma (HCC). These engineered cells demonstrated significantly enhanced anti-tumor efficacy in vitro and in vivo, offering a promising new avenue for HCC treatment.
Area of Science:
- Oncology
- Immunotherapy
- Biotechnology
Background:
- Chimeric antigen receptor T (CAR-T) cell therapy shows promise for hepatocellular carcinoma (HCC) but faces challenges like antigen downregulation.
- Optimizing CAR-T cell therapy is crucial for improving treatment outcomes in HCC patients.
Purpose of the Study:
- To develop novel nanobody (Nb)-derived CAR-T cells targeting FGFR4 for enhanced HCC therapy.
- To evaluate the anti-tumor efficacy and specificity of these engineered CAR-T cells.
Main Methods:
- Constructed an alpaca-derived nanobody phage library targeting FGFR4.
- Screened and validated high-affinity, high-specificity nanobodies against FGFR4.
- Developed and tested nanobody-derived CAR-T cells against HCC in vitro and in vivo.
Main Results:
- Successfully identified nanobodies with high specificity and affinity for FGFR4.
- Nb-derived CAR-T cells demonstrated superior binding to FGFR4 compared to other FGFR family members.
- Engineered CAR-T cells exhibited significantly enhanced anti-tumor efficacy in both in vitro and in vivo models.
Conclusions:
- Nb-derived CAR-T cells targeting FGFR4 show significant potential for treating HCC.
- This approach offers a promising strategy to improve the safety and effectiveness of CAR-T cell therapy for HCC.
- Further exploration of FGFR4-targeted Nb-derived CAR-T cells could advance clinical HCC treatment.
