The goal of this translational project is to optimize targeted T-cells with chimeric antigen receptors (CARs) for use in mesothelioma. CARs are now beginning to show activity in a number of pilot clinical trials, however two issues have emerged that provide a barrier to rapid progress in the field: 1) available preclinical models have not accurately predicted the safety of CARs, and unexpected toxicities from cytokine release and tissue damage has been reported in recent trials;2) high costs and long lead times required for vector production have slowed the clinical application of T cells expressing CARs, and prevent a facile and iterative approach to optimize CAR design and determine the optimal target structures on tumor cells. Our preliminary data establishes that T lymphocytes can be efficiently modified by mRNA electroporation without integration-associated safety concerns, and that repeated infusions of "RNA CAR" T cells mediate robust antitumor effects in preclinical humanized models with disseminated tumor xenografts. Thus, this new platform affords the possibility of rapidly testing potent RNA CARs for antitumor activity, and in the event of toxicity, limiting off-target exposure by discontinuing CAR administration. Because late relapses due to tumor escape variants in pre-clinical models have been identified, it will be important to test combinations of CAR T cells to augment antitumor effects and prevent recurrence.
The specific aims are to 1) Develop a new platform technology using RNA engineering to create "RNA CARs", 2) Conduct experiments using patient material from Project 1 to assess the effects of "third generation" CARs, and 3) Test the anti-tumor activity of a combinatorial CAR-based immunotherapy using CARs specific for mesothelin, high molecular weight melanoma-associated (HMW-MAA) and c-Met for mesothelioma. These studies will test the central hypothesis that multiple CARs (i.e., a "CAR fleet") will improve CAR immunotherapy compared to therapy with "monoclonal" CARs. Furthermore, these studies will establish the safety and feasibility of increasing the therapeutic index of T cells engineered to express powerful activation domains without the associated safety concerns of integrating viral vectors.

Public Health Relevance

Malignant mesothelioma is increasing in prevalence and is currently considered incurable. This project is testing methods to modify lymphocytes so that they can kill tumors efficiently, safely, and specifically. The approach includes providing lymphocytes for a clinical trial, analyzing the trial and conducting new animal experiments to widen the number of targets attacked.

National Institute of Health (NIH)
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University of Pennsylvania
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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

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