Title
CAR T for treatment of acute myeloid leukemia (AML): Chemokine and cytokine targeted switch receptors
Research Area
Life Sciences, Medicine, Hematology and Oncology
Project Summary
Despite significant progress in understanding acute myeloid leukemia (AML) biology, patients with relapsed or refractory AML continue to have dismal outcomes. Translating the success of chimeric antigen receptor (CAR) T cell therapy in B cell malignancies to AML has been impeded by the lack of unique target antigens and the immunosuppressive bone marrow microenvironment orchestrated by AML (1, 2).
In previous work, the Kobold and Subklewe labs have aimed to pioneer next-generation CAR-T cell therapies for AML by leveraging novel target discovery and innovative receptor designs. Using mass spectrometry, RNA sequencing, and computational approaches, we have now identified AML-specific surfaceome and secretome data to guide the development of mono- and dual-targeting CAR-T constructs. Our work focuses on improving T cell specificity and functionality against AML by two complementary strategies:
(1) optimizing antigen recognition through smart targeting approaches, including dual- and split-targeting CARs as well as TCR-transgenic T cells specific for AML-associated (neo-) antigens; and
(2) engineering cytokine and chemokine switch receptors that convert immunosuppressive cues into T cell activation signals, thereby enhancing persistence and anti-leukemic activity in the hostile microenvironment.
Preclinical validation will include AML cell lines, primary AML samples, bone marrow organoids, and advanced in vivo models to assess CAR-T cell fitness, exhaustion, homing, and resistance mechanisms within the bone marrow niche. This comprehensive approach will enable us to select and develop a preclinical lead for translation into an early-phase clinical trial for refractory AML, marking a transformative step toward improving patient outcomes in this challenging disease.