Evaluation of a Fully Human, Hepatitis B Virus-Specific Chimeric Antigen Receptor in an Immunocompetent Mouse Model

Area of Science:

• Immunology
• Virology
• Cell Therapy

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for cancer and chronic infections like hepatitis B virus (HBV).
• Developing fully human CARs is crucial, but their immunogenicity in immunocompetent hosts poses a challenge.
• Existing preclinical models often require immunosuppression, which can worsen chronic hepatitis B (CHB) outcomes.

Purpose of the Study:

• To develop a preclinical mouse model that is immunocompetent and mimics CHB.
• To evaluate the efficacy and safety of a fully human second-generation CAR (S-CAR) targeting HBV-infected cells.
• To establish immune tolerance towards human-derived CAR components.

Main Methods:

• Engineered a fully human second-generation CAR (S-CAR) targeting the HBV envelope protein.
• Co-expressed a truncated epidermal growth factor receptor (EGFRt) safeguard to modulate immune responses.
• Utilized total body irradiation and transfer of T-cells with a signaling-deficient S-CAR decoy and safeguard to induce immune tolerance.

Main Results:

• The fully human S-CAR triggered antibody and T-cell responses in immunocompetent mice, limiting CAR T-cell survival.
• Immune tolerance was successfully induced towards human-derived CAR structures using a specific conditioning regimen.
• Following immune recovery, transferred S-CAR T-cells persisted and demonstrated long-lasting antiviral effector function.

Conclusions:

• A novel preclinical model was established for evaluating fully human CAR T-cell therapy in an immunocompetent setting.
• The developed immune tolerance strategy enables sustained efficacy of CAR T-cells against chronic HBV infection.
• This approach facilitates preclinical assessment of fully human CARs within a functional immune system.