The objective of this application is to monitor the activation and co-stimulation of genetically altered human T-lymphocytes containing chimeric antigen receptors (CARs). T-cells can be genetically engineered to ensure their therapeutic efficacy, and to express markers that can be tracked by non-invasive imaging. Genetic labeling of lymphocytes with nuclear or optical reporter genes allows for non-invasive imaging of T-cell fate in both pre-clinical cancer models and in patients with cancer. This proposal focuses on prostate cancer, based on the genetic targeting of prostate-specific membrane antigen (PSMA). The objectives we are pursuing will increase our knowledge about the dynamics of T-cell activation, co-stimulation and duration of anti-tumor response in vivo. Specifically, using reporter gene imaging in vivo we will explore the role of selected pro- survival/proliferation co-stimulatory pathways which augment the therapeutic potency of genetically targeted T-cells. We hypothesize that genetic labeling of T lymphocytes with novel pathway-specific reporter constructs will allow for repetitive non-invasive monitoring of activation and co-stimulation in T-cells and provide an early assessment of treatment outcome during PSMA-specific adoptive T-cell immunotherapy. The role of imaging will be essential in gaining a better understanding of the duration and magnitude of T-cell activation, persistence and T-cell proliferation. The combined use of therapeutic CARs and imaging reporter genes will provide an innovative research technique and a powerful novel clinical tool in cancer immunotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Molecular Imaging and Probe Development (CMIP)
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Farahani, Keyvan
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Lee, Jason T; Moroz, Maxim A; Ponomarev, Vladimir (2018) Imaging T Cell Dynamics and Function Using PET and Human Nuclear Reporter Genes. Methods Mol Biol 1790:165-180
Moroz, Maxim A; Zanzonico, Pat; Lee, Jason T et al. (2018) Ex Vivo Radiolabeling and In Vivo PET Imaging of T Cells Expressing Nuclear Reporter Genes. Methods Mol Biol 1790:153-163
Serganova, Inna; Moroz, Ekaterina; Cohen, Ivan et al. (2017) Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade. Mol Ther Oncolytics 4:41-54
Lee, Jason T; Zhang, Hanwen; Moroz, Maxim A et al. (2017) Comparative Analysis of Human Nucleoside Kinase-Based Reporter Systems for PET Imaging. Mol Imaging Biol 19:100-108
Liapis, Vasilios; Labrinidis, Agatha; Zinonos, Irene et al. (2015) Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma. Cancer Lett 357:160-169
Moroz, Maxim A; Zhang, Hanwen; Lee, Jason et al. (2015) Comparative Analysis of T Cell Imaging with Human Nuclear Reporter Genes. J Nucl Med 56:1055-60
Ghosh, Arnab; Dogan, Yildirim; Moroz, Maxim et al. (2013) Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity. J Clin Invest 123:2654-62