New Chimeric Antigen Receptors for Treating Hematologic Malignancies

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

In the past year, this project has consisted of testing multiple factors that could affect the function of chimeric antigen receptors (CARs). Chimeric antigen receptors consist of several components, the antigen-recognition moiety that is usually derived from a monoclonal antibody, a extracellular region that connects the antigen-recognition moiety to the transmembrane portion, costimulatory domains such as 4-1BB and CD28, and T cell activation domains such as CD3-zeta. We have constructed 10 new CARs over the past 6 months to test various components of CARs. T cells are transduced with the various CARs by using a gammaretroviral vector, and in vitro assays are carried out. The aim is to find CARs that impart T cells with the ability to kill cancer cells and proliferate without producing large amounts of potentially toxic inflamatory cytokines. We have found that changing the hinge region, costimulatory domains, or T cell activation domains all cause profound differences in CAR function. Following extensive in vitro testing, we will test promising CARs in a murine model within the next few months. This work has lead to a new fully-human anti-CD19 CAR for clinical testing that will start within the next 2-3 months years. Another aspect of this project is identification of new targets for CARs. We are assessing multiple targets that are expressed by leukemia and lymphoma as a main part of this project. We have found important differences in CAR-expressing T-cell biology caused by differences in the hinge and transmembrane regions of CARs. This research was presented at the 2016 American Society of Gene and Cell Therapy meeting, and a manuscript is in preparation.