Rational combinatorial targeting by adapter CAR-T-cells (AdCAR-T) prevents antigen escape in acute myeloid leukemia

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor T-cell (CAR-T) therapy for acute myeloid leukemia (AML) is complicated by shared antigen expression in healthy tissues and significant tumor heterogeneity.
• This heterogeneity leads to challenges in CAR-T efficacy and antigen escape, necessitating advanced therapeutic strategies.

Purpose of the Study:

• To analyze the expression patterns of AML-associated antigens in pediatric AML patient samples.
• To develop and evaluate a novel modular Adapter CAR (AdCAR) platform for multiplexed CAR-T targeting.
• To demonstrate the efficacy of combinatorial AdCAR-T targeting in overcoming antigen heterogeneity and improving therapeutic outcomes in preclinical AML models.

Main Methods:

• Single-cell expression profiling of AML-associated antigens across 30 pediatric AML samples.
• Development of novel adapter molecules (AMs) for the AdCAR platform targeting multiple antigens.
• In vitro and in vivo evaluation of AdCAR-T cell activity against AML models, including patient-derived xenograft (PDX) models.

Main Results:

• Identified CD33, CD38, CD371, IL1RAP, and CD123 as frequently expressed AML antigens with significant inter- and intratumoral variability.
• Demonstrated potent and specific in vitro and in vivo activity of AdCAR-T cells against targeted antigens.
• Showcased that monotargeted CAR-T therapy leads to antigen escape, while combinatorial AdCAR-T targeting effectively cures heterogeneous AML in PDX models.

Conclusions:

• Intratumoral heterogeneity of antigen expression is clinically relevant in pediatric AML, impacting CAR-T therapy outcomes.
• The AdCAR platform offers a flexible and precise approach for combinatorial targeting, enabling effective immunotherapy for heterogeneous AML.
• This study presents a novel precision immunotherapy strategy by utilizing combinatorial targeting with AdCAR-T cells to overcome AML heterogeneity.