The human immune system is a potentially powerful line of defense against cancer. Many biological obstacles exist in cancer patients that thwart tumor-specific T cell expansion, activation, tumor trafficking and killing. Among these is inadequate T cell precursor frequency and low T cell receptor (TCR) binding affinity for tumor antigen. Our hypothesis is that transplantation of high affinity TCR-transduced stem cells will create in the recipient an engineered immune system with potent antitumor biology. Thus, the single goal of this Program Project Grant (PPG) is to test this hypothesis by attempting to control or cure metastatic melanoma. This application is a key part of the strategy to arise from a 3-year collaboration among a score of investigators from four research universities (Caltech, UCLA, USC, UCONN) representing 4 cancer centers, 2 gene medicine programs, 13 departments and several institutes. Our research group will converge the disciplines of immunology, genetic engineering, stem ceil biology, virology, biological imaging and human gene medicine to engineer a tumor-specific human immune system. This will be accomplished in a PPG with 5 projects supported by 3 cores. The PPG will: (1) undertake two first-in-human clinical investigations in which a MART-1 melanoma antigen TCR will be introduced into T cells and hematopoietic stem cells using a lentiviral vector also expressing a PET reporter allowing serial noninvasive imaging of the development of an engineered immune system, (2) fundamental studies of the biology of TCR engineered hematopoietic and embryonic stem cells, and (3) basic biology of TCR engineering. State of the art cores in cell and gene therapy, immunological monitoring and biological imaging will support this science. In this PPG, basic and clinical science will be conducted in parallel, each informing the other;basic scientists and physician-scientists will work together as a team to develop discovery-based science that will change the care of patients.

Public Health Relevance

Lay Summary: This large collaborative research program has as its goal to define the basic biology of genetically engineering the human immune system to recognize and destroy a deadly form of skin cancer -melanoma. Both preclinical animal and human clinical studies will be conducted to determine if blood stem cells can be engineered to produce cancer-killing white blood cells. While focusing on a single human , malignancy, scientific yield from this project will have a significant public health impact for other malignancies and infectious diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Program Officer
Wu, Roy S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
California Institute of Technology
Schools of Arts and Sciences
United States
Zip Code
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