Journal Article

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

Heitjan, Daniel F, Riley, James L, Varela-Rohena, Angel, Lakhal, Mehdi, Hassan, Raffit, Carroll, Richard G, Haines, Kathleen M, Albelda, Steven M, Suhoski, Megan M, Simonet, Jacqueline C, Pastan, Ira, June, Carl H, Carpenito, Carmine, Milone, Michael C

2009

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adoptive immunotherapy / Animals / Antigen (tumor-associated) / antigens / Bcl-x protein / Binding sites / Biological Sciences / Blood / Cancer / Carcinoma / CD137 antigen / CD28 antigen / CD28 Antigens - genetics / CD28 Antigens - immunology / CD28 Antigens - metabolism / Cell Line, Tumor / Cells / chimerism / Cultured cells / Cytokines / engineering / Gene expression / genes / Humans / Immunogenicity / Immunological memory / Immunosurveillance / Immunotherapy / intravenous injection / Lymphocytes / Lymphocytes T / Memory cells / Mesothelin / Mice / Microenvironments / Ovarian cancer / Receptors / secretion / Severe combined immunodeficiency / Signal transduction / Signal Transduction - immunology / Skin & tissue grafts / T cell antigen receptors / T lymphocytes / T-cell receptor / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Tumor burden / Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics / Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology / Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism / Tumors / Xenograft Model Antitumor Assays / Xenografts