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Novel CAR-T cells targeting TRKB for the treatment of solid cancer
Dandan Liang1, Jie Tang1, Bin Sun1
1Department of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Abstract:
Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating blood cancers such as B-cell malignancies, however, its effectiveness as an approach to treat solid tumors remains to be further explored. Here, we focused on the development of CAR-T cell therapies targeting tropomyosin-related kinase receptor B (TRKB), a highly expressed protein that is significantly associated with tumor progression, malignancy, and drug resistance in multiple forms of aggressive solid tumors. To achieve this, we screened brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NTF4) ligand-based CAR-T cells for their efficiency in targeting the TRKB receptor in the context of solid tumors, particularly hepatocellular carcinoma and pancreatic cancer. We demonstrated that TRKB is overexpressed not only in hepatocellular carcinoma and pancreatic carcinoma cell lines but also in cancer stem-like cells (CSCs). Notably, BDNF-CAR T and NTF4-CAR T cells could not only effectively target and kill TRKB-expressing pan-cancer cell lines in a dose-dependent manner but also effectively kill CSCs. We also performed in vivo studies to show that NTF4-CAR T cells have a better potential to inhibit the tumor growth of hepatocellular carcinoma xenografts in mice, compared with BDNF-CAR T cells. Taken together, our findings suggest that CAR-T targeting TRKB may be a promising approach for developing novel therapies to treat solid cancers.
Insights
Chimeric antigen receptor (CAR) T-cell therapy targeting tropomyosin-related kinase receptor B (TRKB) shows promise for solid tumors. CAR-T cells effectively eliminated cancer cells and cancer stem-like cells expressing TRKB in preclinical models.
Area of Science:
- Immunotherapy
- Oncology
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is effective against blood cancers but underexplored for solid tumors.
- Tropomyosin-related kinase receptor B (TRKB) is linked to solid tumor progression, malignancy, and drug resistance.
- Targeting TRKB presents a potential strategy for novel solid tumor treatments.
Purpose of the Study:
- To develop and evaluate CAR-T cell therapies targeting the TRKB receptor in solid tumors.
- To assess the efficacy of brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NTF4) ligand-based CAR-T cells against TRKB-expressing cancers.
- To investigate the potential of TRKB-targeted CAR-T cells in treating hepatocellular carcinoma and pancreatic cancer.
Main Methods:
- Screening of BDNF- and NTF4-based CAR-T cells for TRKB receptor targeting.
- In vitro assessment of CAR-T cell cytotoxicity against TRKB-expressing cancer cell lines and cancer stem-like cells (CSCs).
- In vivo evaluation of CAR-T cell efficacy in inhibiting hepatocellular carcinoma xenograft tumor growth in mice.
Main Results:
- TRKB is overexpressed in hepatocellular carcinoma and pancreatic cancer cell lines, including CSCs.
- BDNF-CAR T and NTF4-CAR T cells demonstrated dose-dependent killing of TRKB-expressing cancer cells and CSCs.
- NTF4-CAR T cells showed superior inhibition of hepatocellular carcinoma xenograft growth compared to BDNF-CAR T cells in vivo.
Conclusions:
- CAR-T cell therapy targeting TRKB is a promising strategy for treating aggressive solid tumors.
- BDNF- and NTF4-based CAR-T cells exhibit potent anti-tumor activity against TRKB-expressing cancers and CSCs.
- Further development of TRKB-targeted CAR-T cells could lead to novel therapeutic options for patients with solid cancers.
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