Camel nanobody-based B7-H3 CAR-T cells show high efficacy against large solid tumours

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor T (CAR-T) cell therapy is a promising cancer treatment.
• B7-H3 is an emerging target for solid tumors, with distinct IgC and IgV epitope motifs.
• Optimizing CAR-T cell activation through rational epitope targeting is crucial for therapeutic efficacy.

Purpose of the Study:

• To develop novel nanobody-based CAR-T cells targeting the B7-H3 protein.
• To evaluate the anti-tumor efficacy of CAR-T cells targeting specific B7-H3 epitopes (IgC vs. IgV).
• To identify molecular mechanisms underlying potent CAR-T cell activity and persistence.

Main Methods:

• Generation of dromedary camel nanobodies against B7-H3.
• Construction and testing of CAR-T cells utilizing nanobodies targeting IgC or IgV domains.
• In vivo efficacy studies in mouse models with large solid tumors.
• Single-cell transcriptome RNA sequencing and functional T-cell proteomics.

Main Results:

• CAR-T cells targeting the B7-H3 IgC epitope exhibited potent anti-tumor activity against large tumors in female mice.
• CAR-T cells targeting the IgV domain showed less efficacy.
• CAR-T cells targeting the IgC epitope displayed enhanced T cell signaling and significant tumor infiltration.
• Identification of key upregulated genes associated with polyfunctional CAR-T cell persistence.

Conclusions:

• The specific epitope targeted by CAR-T cells significantly influences anti-tumor activity.
• Nanobody-based CAR-T cells targeting the B7-H3 IgC epitope represent a viable strategy for solid tumor immunotherapy.
• Understanding epitope-specific CAR-T cell responses can guide the development of more effective cancer therapies.