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Engineered T cells kill tumors but spare normal tissue in an animal model
Date:4/7/2013

PHILADELPHIA The need to distinguish between normal cells and tumor cells is a feature that has been long sought for most types of cancer drugs. Tumor antigens, unique proteins on the surface of a tumor, are potential targets for a normal immune response against cancer. Identifying which antigens a patient's tumor cells express is the cornerstone of designing cancer therapy for that individual. But some of these tumor antigens are also expressed on normal cells, inching personalized therapy back to the original problem.

T cells made to express a protein called CAR, for chimeric antigen receptor, are engineered by grafting a portion of a tumor-specific antibody onto an immune cell, allowing them to recognize antigens on the cell surface. Early first-generation CARs had one signaling domain for T-cell activation. Second-generation CARs are more commonly used and have two signaling domains within the immune cell, one for T-cell activation and another for T- cell costimulation to boost the T cell's function.

Importantly, CARs allow patients' T cells to recognize tumor antigens and kill certain tumor cells. A large number of tumor-specific, cancer-fighting CAR T cells can be generated in a specialized lab using patients' own T cells, which are then infused back into them for therapy. Despite promising clinical results, it is now recognized that some CAR-based therapies may involve toxicity against normal tissues that express low amounts of the targeted tumor-associated antigen.

To address this issue, Daniel J. Powell Jr., PhD, research assistant professor of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, and director of the Cellular Therapy Tissue Facility, developed an innovative dual CAR approach in which the activation signal for T cells is physically dissociated from a second costimulatory signal for immune cells. The two CARs carry different antigen specificity -- mesothelin and a-folate
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-459-0544
University of Pennsylvania School of Medicine
Source:Eurekalert

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