Cancers
Developing a Dual-Targeting CD33/CD70 CAR T-Cell Strategy Against Acute Myeloid Leukemia to Overcome Tumor Heterogeneity
By Emily C Sullivan, Nabil Saleem, Areeba A. Hashmi and 5 others.
Abstract
Background
Acute myeloid leukemia (AML) remains the deadliest form of leukemia in children and adults despite therapeutic advances in recent decades. Chimeric antigen receptor (CAR) T-cell therapy is one such therapeutic approach that has been explored preclinically and clinically in AML; however, its efficacy is limited by antigen heterogeneity. To overcome this roadblock, we propose a dual-targeting CAR T-cell strategy, targeting the AML-associated antigens CD33 and CD70.
Methods
To recapitulate tumor heterogeneity, we genetically edited the AML cell line Molm-13 using CRISPR-Cas9 to generate distinct sublines, namely CD33+/CD70−, CD33−/CD70+, and CD33+/CD70+. Two dual-targeting CAR T-cell approaches were developed: a “pooled” product, in which CAR T cells directed towards CD33 or CD70 are combined and co-administered, and a “co-transduced” product, wherein one population of T cells is transduced with both CD33-CAR- and CD70-CAR-encoding viral vectors.