TGF-β/IL-7 Chimeric Switch Receptor-Expressing CAR-T Cells Inhibit Recurrence of CD19-Positive B Cell Lymphoma

Area of Science:

• Immunology
• Cancer Biology
• Cell Therapy

Background:

• Chimeric antigen receptor (CAR)-T cell therapy shows promise for hematologic malignancies but faces challenges in solid tumors due to immunosuppressive tumor microenvironments.
• Transforming growth factor-beta (TGF-β) is a key immunosuppressive cytokine that limits the efficacy of T cell-based therapies.

Purpose of the Study:

• To develop and evaluate a novel CAR-T cell strategy for inhibiting B cell lymphoma recurrence by co-expressing a CD19-specific CAR and a chimeric switch receptor (tTRII-I7R).
• To engineer T cells that can convert immunosuppressive TGF-β signaling into immune-activating IL-7 signaling, thereby enhancing anti-tumor immunity.

Main Methods:

• Co-expression of a CD19 CAR and a TGF-β/IL-7 chimeric switch receptor (tTRII-I7R) in T cells (CD19 CAR-tTRII-I7R-T cells).
• Assessment of TGF-β effects using western blotting for phosphorylated SMAD2 levels.
• Evaluation of target-specific cytotoxicity via Eu-TDA assay.
• In vivo anti-tumor efficacy analysis in Daudi tumor-bearing NSG mice.

Main Results:

• In vitro, CD19 CAR-tTRII-I7R-T cells exhibited reduced phosphorylated SMAD2 levels and enhanced target-specific cytotoxicity in the presence of TGF-β1 compared to controls.
• In vivo studies demonstrated significantly prolonged overall survival and recurrence-free survival in mice treated with CD19 CAR-tTRII-I7R-T cells.

Conclusions:

• CD19 CAR-tTRII-I7R-T cell therapy represents a promising strategy for achieving durable, TGF-β-resistant anti-tumor effects against B cell lymphoma.
• This approach holds potential for improving clinical outcomes in patients with B cell malignancies by overcoming tumor-induced immunosuppression.