TY - JOUR
T1 - Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains
AU - Carpenito, Carmine
AU - Milone, Michael C.
AU - Hassan, Raffit
AU - Simonet, Jacqueline C.
AU - Lakhal, Mehdi
AU - Suhoski, Megan M.
AU - Varela-Rohena, Angel
AU - Haines, Kathleen M.
AU - Heitjan, Daniel F.
AU - Albelda, Steven M.
AU - Carroll, Richard G.
AU - Riley, James L.
AU - Pastan, Ira
AU - June, Carl H.
PY - 2009/3/3
Y1 - 2009/3/3
N2 - 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-XL, and secrete multiple cytokines, all features characteristic of central memory T cells. When transferred intratumorally or intravenously into NOD/scid/IL2rγ-/- 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.
AB - 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-XL, and secrete multiple cytokines, all features characteristic of central memory T cells. When transferred intratumorally or intravenously into NOD/scid/IL2rγ-/- 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.
KW - Adoptive immunotherapy
KW - Chimeric receptor
KW - Mesothelin
UR - http://www.scopus.com/inward/record.url?scp=62549097817&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=62549097817&partnerID=8YFLogxK
U2 - 10.1073/pnas.0813101106
DO - 10.1073/pnas.0813101106
M3 - Article
C2 - 19211796
AN - SCOPUS:62549097817
SN - 0027-8424
VL - 106
SP - 3360
EP - 3365
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -