Novel adoptive T cell therapies have enabled long lasting objective clinical responses in a significant proportion of patients with metastatic melanoma. Treatment efficacy and availability could be further improved by ex vivo genetic modification of lymphocytes allowing generation of large numbers of cells with enhanced anti-tumor function. The development of such adoptive cell transfer immune therapies is critically dependent on the availability of tools to track the distribution of genetically modified lymphocytes following transplantation in melanoma patients. Work by Program Project Grant (PPG) Investigators in animal models of cancer and in humans has demonstrated that this goal could be accomplished using novel molecular imaging techniques such as Positron Emission Tomography (PET). To visualize the distribution of genetically modified T lymphocytes and Hematopoietic Stem Cells transplanted in melanoma patients, these cells will be engineered to express a PET reporter gene derived from the Herpes Simplex Virus 1 thymidine kinase (HSVI-tk). HSVI-tk has been used extensively in clinical trials as a """"""""suicide gene"""""""" and has a very high affinity for the PET probe (9-[4-[(18)F]fluoro-3-(hydroxymethyl)-butyl]guanine) (9(18)'F]FHBG). [9(18)F]FHBG administered in trace amounts accumulates specifically in cells expressing HSVI-tk and resulting signals can be detected by PET. We will use this technique for in vivo """"""""counting"""""""" of genetically modified cells at various sites throughout the body, including lymphoid organs and metastatic melanoma deposits. Such measurements cannot be performed using conventional technologies and could provide eariy prediction markers for therapeutic responses. To support imaging studies by PPG Investigators, we propose to establish a Biological Imaging Core for noninvasive monitoring of immune responses. This Core will complement state-of-the-art 'in vitro'immUne monitoring measurements described in Core A and will enable PPG Investigators to pertorm preclinical and clinical 'in vivo'immune monitoring studies using multiple imaging modalities. The proposed Core will take advantage of the unique expertise and infrastructure for functional and anatomical tomographic imaging already available at UCLA and will also coordinate preclinical imaging experiments performed at other participating institutions. We envision that the Imaging Core will help cement long-term interactive multi-institutional collaborations involving experts in imaging, gene therapy, basic and clinical immunology, who are at the forefront of cancer immunotherapy transitional research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA132681-01A2
Application #
7782254
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2009-12-01
Budget End
2011-02-28
Support Year
1
Fiscal Year
2010
Total Cost
$355,332
Indirect Cost
Name
California Institute of Technology
Department
Type
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Cheng, Zhi; Wei, Runhong; Ma, Qiuling et al. (2018) In Vivo Expansion and Antitumor Activity of Coinfused CD28- and 4-1BB-Engineered CAR-T Cells in Patients with B Cell Leukemia. Mol Ther 26:976-985
Bethune, Michael T; Li, Xiao-Hua; Yu, Jiaji et al. (2018) Isolation and characterization of NY-ESO-1-specific T cell receptors restricted on various MHC molecules. Proc Natl Acad Sci U S A 115:E10702-E10711
Rohrs, Jennifer A; Zheng, Dongqing; Graham, Nicholas A et al. (2018) Computational Model of Chimeric Antigen Receptors Explains Site-Specific Phosphorylation Kinetics. Biophys J 115:1116-1129
Gee, Marvin H; Han, Arnold; Lofgren, Shane M et al. (2018) Antigen Identification for Orphan T Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes. Cell 172:549-563.e16
Bryson, Paul D; Han, Xiaolu; Truong, Norman et al. (2017) Breast cancer vaccines delivered by dendritic cell-targeted lentivectors induce potent antitumor immune responses and protect mice from mammary tumor growth. Vaccine 35:5842-5849
Bethune, Michael T; Comin-Anduix, Begoña; Hwang Fu, Yu-Hsien et al. (2017) Preparation of peptide-MHC and T-cell receptor dextramers by biotinylated dextran doping. Biotechniques 62:123-130
Siegler, Elizabeth L; Kim, Yu Jeong; Chen, Xianhui et al. (2017) Combination Cancer Therapy Using Chimeric Antigen Receptor-Engineered Natural Killer Cells as Drug Carriers. Mol Ther 25:2607-2619
Han, Xiaolu; Bryson, Paul D; Zhao, Yifan et al. (2017) Masked Chimeric Antigen Receptor for Tumor-Specific Activation. Mol Ther 25:274-284
Fendler, Wolfgang Peter; Barrio, Martin; Spick, Claudio et al. (2017) 68Ga-DOTATATE PET/CT Interobserver Agreement for Neuroendocrine Tumor Assessment: Results of a Prospective Study on 50 Patients. J Nucl Med 58:307-311
Han, Xiaolu; Cinay, Gunce E; Zhao, Yifan et al. (2017) Adnectin-Based Design of Chimeric Antigen Receptor for T Cell Engineering. Mol Ther 25:2466-2476

Showing the most recent 10 out of 71 publications