Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy.

Area of Science:

• Immunology
• Cell Therapy
• Glycobiology

Background:

• Allogeneic chimeric antigen receptor (CAR)-T cell therapy faces challenges with T cell persistence and immune rejection.
• Modulating T cell surface properties is crucial for overcoming these limitations in universal CAR-T applications.

Purpose of the Study:

• To investigate the role of signal peptide peptidase-like 3 (SPPL3) in T cell immune evasion.
• To evaluate the safety and efficacy of SPPL3-deleted allogeneic CAR-T cells in preclinical and clinical settings.

Main Methods:

• Deletion of SPPL3 in primary T cells to alter glycan profiles and assess immune evasion.
• Development and testing of SPPL3-null, T cell receptor (TCR)-deficient and TCR-sufficient anti-CD19 CAR-T cells.
• Phase I clinical trial (NCT06014073) in patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL).

Main Results:

• SPPL3 deletion resulted in glycan-mediated immune evasion, reducing allogeneic T cell immunity without compromising CAR functionality.
• Phase I trial of SPPL3-null, TCR-deficient CAR-T cells met safety endpoints, with manageable cytokine release syndrome (CRS).
• SPPL3-null, TCR-sufficient CAR-T cells showed no graft-versus-host disease signs in compassionate care cases.

Conclusions:

• SPPL3 deletion is a viable strategy for glycan shielding, enhancing immune evasion in allogeneic CAR-T cells.
• This approach holds promise for developing safer and more effective universal CAR-T therapies.
• TCR's role in T cell persistence was highlighted, guiding further optimization of CAR-T cell design.