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

TLDR

Mesothelin is over‑expressed on many carcinomas, making it an attractive immunotherapy target. The study engineered T cells to express a high‑affinity chimeric receptor targeting mesothelin. Lentiviral vectors delivered a single‑chain variable fragment that binds mesothelin and is fused to TCR‑zeta, CD28, and CD137 signaling domains. The engineered T cells proliferated, expressed Bcl‑XL, secreted cytokines, and when injected into mice bearing large tumors, reduced tumor burden and sometimes achieved complete eradication at low effector‑to‑target ratios, with CD137 signaling enhancing cytokine secretion and persistence, underscoring their potential for treating poorly immunogenic cancers.

Abstract

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/IL2r γ −/− 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.