. Genetic manipulation of the human immune system is a powerful approach to combating infectious diseases and cancers. Clinically, the most common cell based therapeutic approach currently used is hematopoietic stem cell (HSC) transplantation. The possibility of stably introducing specific T cell receptors (TCRs) into stem cells to generate T lymphocytes targeting specific antigens of choice opens doors to new and exciting life-long vaccine and therapeutic strategies. Human embryonic stem cells (hESC) and the recently-described induced pluripotent stem (IPS) cells, have the potential to revolutionize transplant technology. The theoretical ability of these cells to differentiate into any cell type in the body opens the possibility of improved cell replacement, organ replacement or genetic therapies. Induced pluripotent stem cells have a particular attraction, in that they can theoretically be derived from individual patients and will thus express identical HLA molecules, so they would not be rejected by the patient's immune response. We have demonstrated that hESC can be induced to differentiate into cells of the T lineage, and that IPS cells also have hematopoietic potential. New genetic material introduced into these cells can be expressed throughout hematopoietic differentiation. Thus the potential for adaptation of these stem cells to clinical use is especially true in regards to genetic manipulation of the immune system. The possibility of using these totipotent stem cells has many advantages over the use of HSC, including ability to culture extensively and ease of genetic manipulation, however there are many gaps in our knowledge regarding control of differentiation into specialized mature cell types. Development of model systems to optimize and study hESC and IPS generation into functional T cells could be very helpful for advancing our ability to genetically manipulate immune responses. This proposal will focus on pre-clinical studies optimizing the generation, from totipotent stem cells, of human T lymphocytes directed to target human melanoma, by virtue of expression of TCRs specific for melanoma antigens. These studies will interact with other components in this Program Project to provide proof-of-principle that hESC and/or IPS can be used to manipulate the immune system to specifically target cancer by pursuing the following specific aims: 1) Develop melanoma-specific cytotoxic T cells from human embryonic and induced pluripotent stem cells;2) Determine how expression of MART-1 TCR influences thymopoietic potential of hESC and IPS cells;3) Develop T-cell specific expression systems to optimize distribution of TCR expression in progeny of hESC and IPS. We hope that together with the other components of this Program Project we will provide important pre-clinical information that cancer-specific T cells can be generated from these versatile stem cells, and that this approach may have potential for treating melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA132681-04
Application #
8448002
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$288,409
Indirect Cost
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

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