New Chimeric Antigen Receptors for Treating Hematologic Malignancies

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In the past year, this project has consisted of testing multiple factors that could affect the function of chimeric antigen receptors (CARs). First we compared lentiviral vector to the gammaretroviral vector that we have used in our current clinical trials. T cells transduced with the lentiviral vector had shorter duration of CAR expression; therefore, we have decided to perform future work with the gammaretroviral vector. Chimeric antigen receptors consis to several components, the antigen-recognition moiety that is usually derived from a monoclonal antibody, a hinge 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 year. This work is all at early stages, but hopefully it will lead to improved CARs for clinical testing within the next 2-3 years.