SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors

Area of Science:

• Immunology
• Cancer Biology
• Cell Therapy

Background:

• Chimeric antigen receptor T (CAR-T) cell therapy shows promise in hematological cancers but faces challenges in solid tumors.
• T-cell exhaustion and cytokine release syndrome limit CAR-T efficacy and safety in solid tumors.
• Transforming growth factor-beta (TGF-β) drives immunosuppression and cytokine production in the tumor microenvironment (TME).

Purpose of the Study:

• To investigate the potential of coexpressing SMAD7 with a HER2-targeted CAR in T cells to overcome TME-induced exhaustion and reduce toxicity.
• To evaluate the impact of SMAD7 on CAR-T cell function, cytokine production, and anti-tumor activity in solid tumor models.

Main Methods:

• Engineered T cells coexpressing a HER2-targeted CAR and SMAD7 were generated.
• Cytolytic efficacy, resistance to TGF-β-induced exhaustion, and cytokine production were assessed.
• CAR-T cell infiltration and activation in patient-derived tumor organoids were evaluated.
• Tumor growth inhibition and survival were monitored in tumor-challenged mice.

Main Results:

• SMAD7-engineered CAR-T cells exhibited enhanced cytolytic activity and resistance to TGF-β-induced exhaustion.
• SMAD7 significantly reduced inflammatory cytokine production by CAR-T cells.
• SMAD7 downregulated TGF-β receptor I, disrupting TGF-β and NF-κB pathway crosstalk.
• These CAR-T cells demonstrated sustained tumor inhibition, improved survival in mice, and enhanced infiltration in tumor organoids.

Conclusions:

• Coexpression of SMAD7 with CAR-T cells represents a viable strategy to enhance efficacy and safety for solid tumor treatment.
• SMAD7 mitigates T-cell exhaustion and systemic toxicity, overcoming the immunosuppressive TME.
• This approach holds promise for improving CAR-T cell therapy in challenging solid tumor indications.