This project will address the therapy of mesothelin expressing tumors by developing and testing engineered? T cells with potent antitumor cytotoxicity. Mesothelin is a tumor-associated antigen that is frequently over? expressed on mesothelioma, non-small cell lung cancer, pancreatic and ovarian cancers. The strategy to be? used is the """"""""T-body"""""""" approach, which employs genetically reprogrammed, patient-derived lymphocytes? transfected with a novel chimeric receptor that contains combinations of the signal transduction domains of? 4-1BB (CD137), CD28, and CD3zeta as well as anti-mesothelin scFv (anti-meso-CD28-41BB-zeta). The central? hypothesis to be tested is that previous trials of adoptive therapy for cancer have used insufficient numbers? of cytotoxic T lymphocytes (CTL) that have shown inadequate engraftment, persistence and effector? function to self antigens. Presently, we are the only laboratory in the world that is actively testing lentiviral? modified T cells in the clinic, and in that trial we have demonstrated safety and prolonged lentiviral gene? transfer. The following three specific aims will test the hypothesis that engineered human T cells expressing? an anti-mesothelin-CD28-41BB-zeta chimeric receptor will have potent antitumor activity in vitro and in vivo by:? (1) developing and optimizing the anti-meso scFv vector. The avidity and the cytosolic signaling modules will? be optimized to obtain highly efficient lentiviral vectors that retarget T cells to specifically kill tumor cells that? express mesothelin at low effector to target ratios in vitro; (2) carrying out in vitro experiments to optimize? the effector functions of anti-mesothelin scFv CD28-41BB-zeta T bodies. Experiments will determine optimal? conditions for redirected T cell serial killing, cytokine production and proliferation, and compare this to? natural MHC restricted CTLs; and (3) performing in vivo experiments in immunodeficient NOD/SCID/beta2null? mice xenografted with human tumors that express mesothelin. These experiments will test the hypothesis? that vectors with high affinity scFv receptors and 4-1BB and CD28 signaling modules will have the most? potent anti-tumor effects. Finally, the engraftment, persistence and antitumor effects of chimeric T cells? given by intravenous and intraperitoneal routes will be compared using bioluminescence imaging. In? summary, an outstanding team of basic and translational scientists has been assembled that will develop? and test a universal T cell receptor to target some of the most common and drug resistant tumors.? Lay Description. A common reason for failure of immunotherapy of epithelial tumors is that the? immune system does not generate sufficient numbers of T cells to eradicate the tumor cells. It is now? possible to use lentiviral vector technology to engineer T cells with potent and specific antitumor effects.? This project will evaluate engineered T cells that target mesothelin that is overexpressed on both uncommon? tumors such as mesothelioma and a variety of commonly lethal tumors including pancreatic, ovarian and? non-small cell lung carcinoma.?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
Aggarwal, Charu; Haas, Andrew R; Metzger, Susan et al. (2018) Phase I Study of Intrapleural Gene-Mediated Cytotoxic Immunotherapy in Patients with Malignant Pleural Effusion. Mol Ther 26:1198-1205
Moon, Edmund K; Wang, Liang-Chuan S; Bekdache, Kheng et al. (2018) Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines. Oncoimmunology 7:e1395997
Klampatsa, Astero; Haas, Andrew R; Moon, Edmund K et al. (2017) Chimeric Antigen Receptor (CAR) T Cell Therapy for Malignant Pleural Mesothelioma (MPM). Cancers (Basel) 9:
Moon, Edmund K; Ranganathan, Raghuveer; Eruslanov, Evgeniy et al. (2016) Blockade of Programmed Death 1 Augments the Ability of Human T Cells Engineered to Target NY-ESO-1 to Control Tumor Growth after Adoptive Transfer. Clin Cancer Res 22:436-47
Liu, X; Barrett, D M; Jiang, S et al. (2016) Improved anti-leukemia activities of adoptively transferred T cells expressing bispecific T-cell engager in mice. Blood Cancer J 6:e430
Liu, Xiaojun; Ranganathan, Raghuveer; Jiang, Shuguang et al. (2016) A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors. Cancer Res 76:1578-90
O'Hara, Mark; Stashwick, Caitlin; Haas, Andrew R et al. (2016) Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy. Immunotherapy 8:449-60
Sterman, Daniel H; Alley, Evan; Stevenson, James P et al. (2016) Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFN? Combined with Chemotherapy. Clin Cancer Res 22:3791-800
Newick, Kheng; O'Brien, Shaun; Sun, Jing et al. (2016) Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization. Cancer Immunol Res 4:541-51
Andy, Uduak U; Harvie, Heidi S; Smith, Ariana L et al. (2015) Validation of a self-administered instrument to measure adherence to anticholinergic drugs in women with overactive bladder. Neurourol Urodyn 34:424-8

Showing the most recent 10 out of 85 publications