Engineering Functionality Optimized fully human B7-H3 CAR T Cells for Enhanced Solid Tumor Therapy.

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• B7-H3 is a tumor-associated antigen overexpressed in various solid tumors.
• Current B7-H3 chimeric antigen receptor (CAR) T cell therapies utilize murine-derived antibodies, risking immune rejection.
• Existing CAR T cell therapies face challenges due to immunogenicity of non-human antibody sequences.

Purpose of the Study:

• To generate fully human B7-H3-specific single-chain variable fragments (scFvs) for improved CAR T cell therapy.
• To evaluate the efficacy and safety of novel human B7-H3 CAR T cells in preclinical solid tumor models.

Main Methods:

• In vitro phage display technology was employed to isolate fully human B7-H3-specific scFvs.
• CAR T cells engineered with the lead human binder, Y111, were tested in pancreatic cancer, neuroblastoma, and glioblastoma xenograft models.
• Comparative analysis of Y111-based CAR T cells against murine-derived CAR T cells (376.96 and MGA271).

Main Results:

• CAR T cells incorporating the Y111 binder were well-tolerated in xenograft models.
• Y111-based CAR T cells exhibited superior antitumor activity compared to 376.96- and MGA271-based CARs.
• Y111 CAR treatment resulted in complete responses, tumor rejection, and significant survival benefits.

Conclusions:

• The fully human B7-H3 binder Y111 is a promising candidate for developing next-generation CAR T cell therapies.
• Y111-based CAR T cells offer a potentially safer and more effective treatment strategy for solid tumors.
• This study highlights the advantage of fully human binders in overcoming immunogenicity issues in CAR T cell therapy.