Richard G. Carroll

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.

Active suppression by T regulatory cells plays an important role in the down-regulation of T cell responses to foreign and self-Ags. Thus far, the potential role of CD4(+)CD25(+) T cells in human tumors has not been reported. In this work we show that lung tumors contain large numbers of these cells and that they have constitutive high-level expression of CD152 (CTLA-4). Furthermore, the CD4(+)CD25(+) T cells mediate potent inhibition of autologous T cell proliferation. Finally, regulatory T cells from patient tumors failed to inhibit the proliferation of allogeneic T cells. Together these results suggest that the CD4(+)CD25(+) T cells found in lung tumors selectively inhibit the host immune response and therefore could contribute to the progression of lung cancer.