Engineering functionality-optimized fully human B7-H3 CAR T cells for enhanced solid tumor therapy

Area of Science:

• Oncology
• Immunotherapy
• Biotechnology

Background:

• B7-H3 is a cell surface protein frequently overexpressed in solid tumors.
• Current chimeric antigen receptor (CAR) T cell therapies targeting B7-H3 utilize murine-derived antibodies, risking immune rejection.
• Existing humanized CARs may still contain immunogenic residues.

Purpose of the Study:

• To develop fully human single-chain variable fragments (scFvs) for B7-H3 CAR T cell therapy.
• To evaluate the safety and efficacy of a novel human B7-H3 CAR T cell therapy in preclinical cancer models.

Main Methods:

• In vitro phage display was used to generate fully human B7-H3-specific scFvs.
• CAR T cells incorporating the lead human binder, Y111, were tested in pancreatic cancer, neuroblastoma, and glioblastoma xenograft models.
• Comparative analysis with existing B7-H3 CARs (376.96 and MGA271) was performed.

Main Results:

• CAR T cells with the Y111 binder were well-tolerated in xenograft models.
• Y111-based CAR T cells demonstrated superior antitumor activity compared to murine-derived CARs.
• Complete tumor responses, rejection, and significant survival benefits were observed with Y111 CAR treatment.

Conclusions:

• The fully human B7-H3 binder Y111 is a promising candidate for next-generation CAR T cell therapy.
• Y111 CAR T cells offer enhanced safety and efficacy for treating solid tumors.
• This approach overcomes immunogenicity issues associated with non-human CAR components.