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

receptor. Mesothelin is primarily associated with mesothelioma and ovarian cancer, and a-folate receptor with ovarian cancer.

Powell likens this dual CAR approach to having two different gas pedals, one for starting the immune system and a second for revving it up. Dual CAR T cells are more selective for tumor cells since their full activity requires interaction with both antigens, which are only co-expressed on tumor cells, not normal tissue.

Dual CAR T cells showed weak cytokine production against target cells expressing only one tumor-associated antigen in lab assays, similar to first-generation CAR T cells bearing the CD3 activation domain only, but demonstrated enhanced cytokine production upon encountering natural or engineered tumor cells expressing both antigens, equivalent to second-generation CAR T cells with dual, but unseparated signaling.

In a mouse model of human ovarian cancer, T cells with the dual-signaling CARs persisted at high numbers in the blood, accumulated in tumors, and showed potent anti-cancer activity against human tumors. Dual CAR T cells were equivalent to second-generation CAR T cells in activity against tumors bearing two antigens. However, the dual-signaling CAR T cells did not react vigorously with normal tissue expressing one antigen while second- generation CAR T cells did.

"This new dual-specificity CAR approach can enhance the therapeutic efficacy of CAR T cells against cancer while minimizing reactivity against normal tissues," says Powell.

Their findings have been published in the inaugural issue of Cancer Immunology Research, the newest journal from the American Association for Cancer Research.


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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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