Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains.
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.
Carpenito
Carmine
C
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Milone
Michael C
MC
Hassan
Raffit
R
Simonet
Jacqueline C
JC
Lakhal
Mehdi
M
Suhoski
Megan M
MM
Varela-Rohena
Angel
A
Haines
Kathleen M
KM
Heitjan
Daniel F
DF
Albelda
Steven M
SM
Carroll
Richard G
RG
Riley
James L
JL
Pastan
Ira
I
June
Carl H
CH
D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D000090204:Mesothelin; D051379:Mice; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D018106:CD28 Antigens; C000715528:Msln protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000090204:Mesothelin