Ravindra MajetiPhD, MD
Board of Trustees of the Leland Stanford Junior University
Project Term: July 1, 2018 - June 30, 2021
AML is an aggressive cancer of blood progenitors with poor clinical outcomes. We propose to develop and test in pre-clinical models chimeric antigen receptor (CAR)-modified T cells directed against CD93 expressed on human AML stem cells. We recently discovered expression of CD93 on a variety of AML cells, but not on blood stem and progenitor cells or most normal tissues, making it a good CAR T cell target. Our goal is to develop a CAR T cell candidate that can be brought into clinical trials.
Acute myeloid leukemia (AML) is an aggressive cancer of the blood and bone marrow with poor overall outcomes. Standard of care for the treatment of AML consists of high dose chemotherapy, often including bone marrow transplantation, but has not changed for decades. Novel, less-toxic, and more effective therapies are needed for this devastating disease. Here, we propose to develop and test in pre-clinical models chimeric antigen receptor (CAR)-modified T cells directed against CD93 expressed on human AML stem cells. We recently discovered expression of CD93 on AML cells from a variety of clinical subtypes and determined that this antigen is not expressed on blood stem or progenitor cells, or on most normal tissues, making it a good target for CAR T cells. We have generated a humanized antibody against CD93 that will be used to create CAR constructs that will be tested for activity against human AML. Pre-clinical testing will include both in vitro T cell killing assays and in vivo leukemia models, facilitating selection of a lead clinical CAR T cell candidate. The CAR T cell approach has shown enormous promise and activity for the treatment of acute lymphoblastic leukemia (ALL), but thus far, no CAR has been developed for AML. Our approach in targeting CD93 on human AML cells has the potential to bring major clinical benefit to patients without significant toxicity. Importantly, this proposal seeks to develop a leading CAR T cell candidate that could be directly brought forward into clinical trials.