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 #
5P01CA132681-05
Application #
8627569
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$360,372
Indirect Cost
$22,681
Name
California Institute of Technology
Department
Type
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Fendler, Wolfgang Peter; Barrio, Martin; Spick, Claudio et al. (2016) 68Ga-DOTATATE PET/CT interobserver agreement for neuroendocrine tumor assessments: results from a prospective study on 50 patients. J Nucl Med :
Boschi, Stefano; Lee, Jason T; Beykan, Seval et al. (2016) Synthesis and preclinical evaluation of an Al(18)F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand. Eur J Nucl Med Mol Imaging 43:2122-2130
Bethune, Michael T; Gee, Marvin H; Bunse, Mario et al. (2016) Domain-swapped T cell receptors improve the safety of TCR gene therapy. Elife 5:
Bluemel, Christina; Krebs, Markus; Polat, Bülent et al. (2016) 68Ga-PSMA-PET/CT in Patients With Biochemical Prostate Cancer Recurrence and Negative 18F-Choline-PET/CT. Clin Nucl Med 41:515-21
Fiacco, Stephen V; Kelderhouse, Lindsay E; Hardy, Amanda et al. (2016) Directed Evolution of Scanning Unnatural-Protease-Resistant (SUPR) Peptides for in Vivo Applications. Chembiochem 17:1643-51
Fendler, Wolfgang Peter; Czernin, Johannes; Herrmann, Ken et al. (2016) Variations in PET/MRI Operations: Results from an International Survey Among 39 Active Sites. J Nucl Med 57:2016-2021
Spick, Claudio; Herrmann, Ken; Czernin, Johannes (2016) 18F-FDG PET/CT and PET/MRI Perform Equally Well in Cancer: Evidence from Studies on More Than 2,300 Patients. J Nucl Med 57:420-30
Fang, Jinxu; Hu, Biliang; Li, Si et al. (2016) A multi-antigen vaccine in combination with an immunotoxin targeting tumor-associated fibroblast for treating murine melanoma. Mol Ther Oncolytics 3:16007
Mok, Stephen; Tsoi, Jennifer; Koya, Richard C et al. (2015) Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition. BMC Cancer 15:356
Herrmann, Ken; Bluemel, Christina; Weineisen, Martina et al. (2015) Biodistribution and radiation dosimetry for a probe targeting prostate-specific membrane antigen for imaging and therapy. J Nucl Med 56:855-61

Showing the most recent 10 out of 58 publications