JOURNAL ARTICLE

Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains

Carmine Carpenito, Michael C Milone, Raffit Hassan, Jacqueline C Simonet, Mehdi Lakhal, Megan M Suhoski, Angel Varela-Rohena, Kathleen M Haines, Daniel F Heitjan, Steven M Albelda, Richard G Carroll, James L Riley, Ira Pastan, Carl H June
Proceedings of the National Academy of Sciences of the United States of America 2009 March 3, 106 (9): 3360-5
19211796
Mesothelin is a cell-surface molecule over-expressed on a large fraction of carcinomas, and thus is an attractive target of immunotherapy. A molecularly targeted therapy for these cancers was created by engineering T cells to express a chimeric receptor with high affinity for human mesothelin. Lentiviral vectors were used to express a single-chain variable fragment that binds mesothelin and that is fused to signaling domains derived from T-cell receptor zeta, CD28, and CD137 (4-1BB). When stimulated by mesothelin, lentivirally transduced T cells were induced to proliferate, express the antiapoptotic gene Bcl-X(L), and secrete multiple cytokines, all features characteristic of central memory T cells. When transferred intratumorally or intravenously into NOD/scid/IL2rgamma(-/-) mice engrafted with large pre-established tumors, the engineered T cells reduced the tumor burden, and in some cases resulted in complete eradication of the tumors at low effector-to-target ratios. Incorporation of the CD137 signaling domain specifically reprogrammed cells for multifunctional cytokine secretion and enhanced persistence of T cells. These findings have important implications for adoptive immunotherapy of cancer, especially in the context of poorly immunogenic tumors. Genetically redirected T cells have promise of targeting T lymphocytes to tumor antigens, confer resistance to the tumor microenvironment, and providing immunosurveillance.

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