Tunable universal OR-gated CAR T cells for AML

Area of Science:

• Immunotherapy
• Oncology
• Biotechnology

Background:

• Acute myeloid leukemia (AML) presents significant challenges due to antigen heterogeneity and poor patient prognosis.
• Current treatment strategies often struggle to address the complex antigenic landscape of AML.

Purpose of the Study:

• To develop a novel chimeric antigen receptor (CAR) platform to overcome AML heterogeneity.
• To engineer a combinatorial OR-gate approach targeting both FLT3 and CD33 antigens simultaneously.

Main Methods:

• Utilized a Split, Universal, Programmable (SUPRA) CAR platform enabling tunable activation and multiplexed targeting.
• Developed a combinatorial OR-gate strategy combining FLT3 and CD33 targeting.
• Characterized SUPRA CAR adapter specificity, sensitivity, and dose-response across various cell lines.

Main Results:

• The SUPRA OR gate CAR system demonstrated effective dual-antigen targeting (FLT3 and CD33) in AML models.
• Achieved efficacy comparable to conventional CARs with reduced engineering complexity.
• Identified a therapeutic window minimizing off-target cytotoxicity against hematopoietic stem and progenitor cells.

Conclusions:

• The SUPRA OR gate CAR platform offers a promising strategy for treating antigenically heterogeneous AML.
• This approach presents a potentially safer and more effective therapeutic option for AML patients.