Project 1 focuses on developing reporter gene imaging methods that can be translated into clinical applications. Specifically, we wish to test whether sequential imaging of adoptively transferred antigenspecific T cells can be used to predict responses of targeted tumors, early after transfer, and to identify T cell interactions affecting anti-tumor activity. We propose to initially develop and test a series of vectors encoding both a constitutive and an inducible reporter gene, and to assess their capacity to distinguish subpopulations of EBV-specific T cells during their specific antigen-induced activation-proliferation or apoptosis (Aim 1). We will then evaluate whether and to what degree different subpopulations of transduced antigen-specific T-cells can be distinguished in vivo by sequential imaging of co-administered T-cells, adoptively transferred into NOD/SCID mice bearing human EBV lymphoma xenografts. We will also examine the contributions of different functional subsets of T-cells, transduced to express distinguishable reporter genes, to target and accumulate in EBV lymphoma xenografts, to proliferate and survive in these tumors, and to assess their tumoricidal activity against targeted tumor cells at sequential intervals after adoptive transfer (Aim 2).
In Aim 3, we propose to conduct a phase I clinical trial of EBV-specific T-cells transduced with a new vector encoding two human genes, a mutant LNGFR and the human iodide symporter (hNIS), in the treatment of EBV lymphomas complicating allogeneic hematopoietic progenitor cell transplants or organ allografts. Thereafter, we will incorporate this vector into a phase II trial testing and imaging EBV-specific T-cells differing in repertoire and duration of selection in vitro, as well as in their content of CD4 and CDS T-cells that will be identifiable following their transduction with distinguishable reporter constructs. One of these vectors, termed NIT, is a retroviral vector encoding a biologically inactive mutant of the human nerve growth factor receptor and an IRES-linked HSV-thymidine kinase gene. This vector being used in a current clinical trial. The new dicistronic vector being introduced, is derived from the NIT vector, but substitutes the hNIS gene for HSVItk because HSVItk (and fusion genes incorporating HSVItk) currently in use as reporters are limited by their potential immunogenicity in man. This new dicistronic vector, which exclusively encodes human genes for in vitro selection and in vivo imaging, is likely to be far less immunogenic, and should therefore not compromise the life span of transduced T-cells following adoptive transfer. The planned phase II trial should also provide a direct comparison of the activity and persistence of antigen-specific T-cells selected early or late in the course of in vitro culture.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA086438-09
Application #
7899921
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
9
Fiscal Year
2009
Total Cost
$223,946
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
McDevitt, Michael R; Thorek, Daniel L J; Hashimoto, Takeshi et al. (2018) Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer. Nat Commun 9:1629
Dunphy, Mark P S; Harding, James J; Venneti, Sriram et al. (2018) In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine. Radiology 287:667-675
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
Graham, Nicholas A; Minasyan, Aspram; Lomova, Anastasia et al. (2017) Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Mol Syst Biol 13:914
Lu, Shaohua; Tan, Kay See; Kadota, Kyuichi et al. (2017) Spread through Air Spaces (STAS) Is an Independent Predictor of Recurrence and Lung Cancer-Specific Death in Squamous Cell Carcinoma. J Thorac Oncol 12:223-234
Pankov, Dmitry; Sjöström, Ludvig; Kalidindi, Teja et al. (2017) In vivo immuno-targeting of an extracellular epitope of membrane bound preferentially expressed antigen in melanoma (PRAME). Oncotarget 8:65917-65931
Kim, Kwanghee; Zhang, Hanwen; La Rosa, Stephen et al. (2017) Bombesin Antagonist-Based Radiotherapy of Prostate Cancer Combined with WST-11 Vascular Targeted Photodynamic Therapy. Clin Cancer Res 23:3343-3351
Shrestha, Liza; Patel, Hardik J; Kang, Yanlong et al. (2017) Copper Mediated Coupling of 2-(Piperazine)-pyrimidine Iodides with Aryl Thiols using Cu(I)Thiophene-2-carboxylate. Tetrahedron Lett 58:4525-4531
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
Weidenauer, Lorenz; Wang, Tai; Joshi, Suhasini et al. (2017) Proteomic interrogation of HSP90 and insights for medical research. Expert Rev Proteomics 14:1105-1117

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