The adoptive transfer of T cell receptor (TCR) engineered T cells and hematopoietic stem cells (HSCs) can potentially provide a patient with a large supply of tumor-specific T cells, enhancing immune-based therapies for cancer. A full understanding of the basic biology of these TCR engineered cells will be very valuable to help design a more potent therapy. In this project, we propose to use the B16 melanoma tumor model to conduct a comprehensive study of the Pmel TCR engineered peripheral CDS T cells, CD4 T cells and HSCs. For this purpose, retroviral and lentiviral vectors will be constructed to co-deliver the genes encoding the Pmel TCR and a bioluminescence reporter into the target cells. The in vivo fate of the TCR-engineered T cells and HSCs will be monitored using Bioluminescence Imaging (BLI) in a live animal in real-time. We plan to study the antimelanoma immunity generated by the adoptive transfer of TCR-engineered T cells (Specific Aim1), HSCs (Specific Aim2), and their combination (Specific Aim3). Various conditions for the in vitro TCR transduction, recipient animal pre-conditioning, adoptive transfer, and post-transfer immunization will be evaluated for their contribution to an effective therapy. In particular, we will study the synergy between the anti-tumor CD4 and CDS T cells, and the influence of the CD4+CD25+ regulatory T cells (Tregs) for adoptive therapy. We will also try to enhance the anti-tumor effectiveness of the engineered anti-tumor T cells by co-delivery of an enhancement gene together with the TCR genes into the target cells. From the proposed study, we expect to gain a thorough understanding of the basic biology of TCR-engineered peripheral T cells and HSCs, and the anti-tumor immunity generated through adoptive transfer of these engineered cells. This basic biology will inform the clinical investigations being conducted in Project 1 and Project 3.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA132681-01A2
Application #
7782227
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
$229,435
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
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