New Chimeric Antigen Receptors for Treating Hematologic Malignancies

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The "New Chimeric Antigen Receptors" project consists of 2 parts. In the first part of this project we are attemping to identify chimeric antigen receptors (CARs) with different antigen specificities than the anti-CD19 chimeric antigen receptors that we have extensive experience with. The first step to finding chimeric antigen receptors with new specificities is to find appropriate targets. We are interested in finding antigenic targets on multiple myeloma or hodgkins lymphoma that could be safely and effectively targeted by CARs. We have spent considerable time and resources in the past year screening normal human tissues for expression of candidate antigens. This is a critical first step in developing new targets because if a target is expressed on normal human tissues, targeting it with chimeric-antigen-receptor-expressing T cells could cause significant toxicity. We have been screening normal tissues by quantitative PCR and by immunohistochemistry. We have identified one antigen with very restricted expression on normal tissues. This antigen is expressed by multiple myeloma cells and some hodgkins lymphoma cells. We have constructed 3 new CAR genes that are designed to target this antigen. We will soon test these new CARs in vitro. The second aspect of the "New Chimeric Antigen Receptor" project is to explore the use of lentiviral vectors for transducing T cells with CARs. We have a collaboration with Richard Morgan in the Surgery Branch of the NCI and we have obtained a lentiviral vector called pRRLSIN.cPPT.MSCV.coDMF5.oPRE from Dr. Morgan. We have cloned multipe CAR genes into this lentiviral vector after removing the coDMF5 component from the vector. We are testing the new lentiviral CAR vectors in vitro in hopes of developing a new CAR vector for future clinical trials.