Nanobodies Meet CAR-T: Shaping the Future of Cancer Therapy

Chimeric Antigen Receptor T-cell (CAR-T) therapy is an emerging cellular immunotherapy that genetically modifies T-cells to express Chimeric Antigen Receptors (CARs) on their surfaces. These receptors enable T-cells to recognize and specifically target antigens on the surface of cancer cells, triggering a cytotoxic response. While CAR-T has significantly advanced blood cancer treatment and shown potential in solid tumors, it faces challenges like off-target effects and treatment-related toxicities.

Researchers are exploring novel CAR designs, with nanobody-based CAR-T gaining attention due to its small size, high stability, low immunogenicity, and high specificity.

CAR-T Structure

The basic CAR structure comprises an extracellular target antigen-binding domain (targeting domain), a hinge region, a transmembrane domain, and one or more intracellular signaling domains. The antigen-binding domain, currently dominated by single-chain variable fragments (scFvs), is prone to aggregation and immunogenicity, impacting efficacy.

Nanobodies, or VHHs (Variable Heavy domain of Heavy chain), from camelids and sharks, offer an alternative due to their low immunogenicity, high stability, and lack of aggregation, minimizing off-target effects.

Examples of Nanobody-Based CAR-T Cells

VEGFR2-specific CAR-T Cells

Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) is a receptor located on the surface of endothelial cells, involved in angiogenesis and tumorigenesis, often overexpressed in head and neck squamous cell carcinomas. Studies have shown that second-generation VEGFR2-specific CAR-T cells when co-cultured with VEGFR2-positive target cells, express activation markers CD69 and CD25 on their surfaces and exhibit target antigen-dependent induction of IL-2 and IFN-γ production and secretion. Furthermore, these CAR-T cells demonstrate potential for targeting VEGFR2 overexpression in the tumor vasculature.

HER2-specific CAR-T Cells

Human Epidermal Growth Factor Receptor 2 (HER2), a member of the epidermal growth factor receptor family with tyrosine kinase activity, plays a crucial role in regulating cell proliferation and tumorigenesis signaling pathways in various malignancies. Researchers have successfully expressed HER2-specific CAR-T cells through gene editing technology based on nanobodies in Jurkat cells. These cells exhibit enhanced proliferation, cytokine secretion, and antitumor activity in vitro, outperforming traditional CAR-T cells. Additionally, combining the enhanced targeting capability of nanobodies with third-generation CAR designs can significantly improve T-cell tumor-killing efficacy.

Conclusion

CAR-T cell therapy has demonstrated immense potential in treating refractory hematological malignancies. Traditional tumor therapy using scFv possesses limitations in terms of efficacy and safety. The introduction of nanobodies is a novel avenue. Compared to scFv, nanobodies boast a more stable structure, lower immunogenicity, and a reduced risk of immune exhaustion during CAR-T cell therapy. In 2022, the first CAR-T product based on nanobodies, Ciltacabtagene Autoleucel was approved by the US FDA for the treatment of refractory multiple myeloma, marking a new era of nanobody CAR-T therapy entering clinical application.

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