Project 4;Generation of Anti-Melanoma T cells Derived From Human Embryonic Stem Cells Abstract 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 theorefically be derived from individual patients and will thus express idenfical 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 differenfiafion. 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 genefic manipulafion, 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 funcfional 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 anfigens. These studies will interact with other components in this Program Project to provide poof-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 opfimize 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 informafion 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 #
1P01CA132681-01A2
Application #
7782232
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
$318,349
Indirect Cost
Name
California Institute of Technology
Department
Type
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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
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
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
Hegde, Upendra P; Mukherji, Bijay (2017) Current status of chimeric antigen receptor engineered T cell-based and immune checkpoint blockade-based cancer immunotherapies. Cancer Immunol Immunother 66:1113-1121

Showing the most recent 10 out of 71 publications