This is the A1 amended submission of a third competitive renewal of a translational P01 whose continuing goal is to develop and test novel therapies for malignant pleural mesothelioma (MPM) within the structure of a highly interactive multi-disciplinary group that moves from "bench-to-bedside" and back again. The overall hypothesis is that immuno- and immuno-gene therapy can be used to treat MPM successfully. In the preceding funding period, the Program conducted preclinical work that led to clinical trials using direct intrapleural injection of an adenovirus expressing a type I interferon (Ad.IFN), ultimately leading to a Phase 2 trial, and developed the technology to allow initiation of a clinicl trial using adoptive transfer of genetically modified T-cells that react against the MPM antigen mesothelin. In this proposal, the focus will be on completion of the Phase 2 trial and on moving adoptive T-cell transfer trials forward. The renewal is organized into three projects supported by three Cores. Project 1 (Clinical Trials) will conduct a Phase 2 clinical trial using a combination f intrapleural Ad.IFN and a COX-2 inhibitor with first- or second-line chemotherapy. It will also begin clinical trials using adoptive transfer of gene-modified T-cells. Project 2 (Preclinical Studies) and Project 3 (Genetically Modified T cells) will continue to develop and optimize adoptive immunotherapy for mesothelioma using genetically modified lymphocytes expressing chimeric antigen receptors (CARs). Project 2 will focus on increasing trafficking of T cells into tumors, optimizing combination with chemotherapy, and enhancing T cell function by altering the tumor microenvironment and preventing T cell inactivation. Project 3 will focus on using RNA engineering to create RNA CARs, testing the antitumor activity of combinatorial CAR-based immunotherapy, and conducting experiments using patient material from Project 1 to assess the activity of the transfused T cells. Core A will supply administrative infrastructure. Core B will provide support as the "Tissue Acquisition, Sample Processing, and Pathology Core". Core C will provide biostatistical and data management services. The goal of this P01 is to alter the treatment paradigm for MPM and advance the entire field of adoptive T cell transfer.

Public Health Relevance

Malignant Pleural Mesothelioma is a highly lethal cancer caused by asbestos exposure. Since current treatments are relatively ineffective, new approaches are needed. This project will to use immuno- and immuno-gene therapy to activate the immune system of the patient or to modify the patient's own lymphocytes to treat this disease. Both animal studies and clinical trials are proposed.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01CA066726-17
Application #
8677698
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Timmer, William C
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Maus, Marcela V; Fraietta, Joseph A; Levine, Bruce L et al. (2014) Adoptive immunotherapy for cancer or viruses. Annu Rev Immunol 32:189-225
Singh, Nathan; Liu, Xiaojun; Hulitt, Jessica et al. (2014) Nature of tumor control by permanently and transiently modified GD2 chimeric antigen receptor T cells in xenograft models of neuroblastoma. Cancer Immunol Res 2:1059-70
Wang, Liang-Chuan S; Lo, Albert; Scholler, John et al. (2014) Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res 2:154-66
Barrett, David M; Singh, Nathan; Liu, Xiaojun et al. (2014) Relation of clinical culture method to T-cell memory status and efficacy in xenograft models of adoptive immunotherapy. Cytotherapy 16:619-30
Moon, Edmund K; Wang, Liang-Chuan; Dolfi, Douglas V et al. (2014) Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res 20:4262-73
Beatty, Gregory L; Haas, Andrew R; Maus, Marcela V et al. (2014) Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res 2:112-20
Vonderheide, Robert H; June, Carl H (2014) Engineering T cells for cancer: our synthetic future. Immunol Rev 257:7-13
Fridlender, Z G; Jassar, A; Mishalian, I et al. (2013) Using macrophage activation to augment immunotherapy of established tumours. Br J Cancer 108:1288-97
Baek, Kwan-Hyuck; Bhang, Dongha; Zaslavsky, Alexander et al. (2013) Thrombospondin-1 mediates oncogenic Ras-induced senescence in premalignant lung tumors. J Clin Invest 123:4375-89
Quatromoni, Jon G; Suzuki, Eiji; Okusanya, Olugbenga et al. (2013) The timing of TGF-* inhibition affects the generation of antigen-specific CD8+ T cells. BMC Immunol 14:30

Showing the most recent 10 out of 66 publications