Developing a membrane-proximal CD33-targeting CAR T cell.

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• CD33 is a target for chimeric antigen receptor (CAR) T cell therapy in acute myeloid leukemia (AML).
• Current CAR T cell therapies targeting CD33 have not achieved clinical success.

Purpose of the Study:

• To develop a novel CD33-directed CAR T cell therapy with enhanced efficacy.
• To investigate the impact of targeting membrane-proximal versus membrane-distal CD33 epitopes.

Main Methods:

• Developed a novel CD33-directed CAR T cell (3P14HLh28Z) using a high-affinity binder from membrane-proximal fragment immunization in humanized mice.
• Compared 3P14HLh28Z with clinically validated CAR T cells targeting distal CD33 epitopes in vitro and in vivo models.

Main Results:

• Immunization with the membrane-proximal domain of CD33 was crucial for identifying effective binders.
• 3P14HLh28Z exhibited enhanced in vitro functionality, superior tumor control, and increased overall survival in AML models.
• Increased T cell activation and polyfunctionality correlated with enhanced anti-leukemic efficacy.

Conclusions:

• This study demonstrates that targeting membrane-proximal CD33 epitopes with high-affinity binders yields superior CAR T cell efficacy compared to targeting membrane-distal epitopes.
• Optimizing CAR T cells for functionality in low antigen density and patient-derived models is critical for therapeutic success.