PROJECT 3: TRANSDUCTION OF HEMATOPOIETIC STEM CELLS FOR ENHANCED IMMUNOTHERAPY OF MELANOMA. Project Leaders: Donald B. Kohn, James S. Economou, Antoni Ribas, Jerome A. Zack ABSTRACT Immunotherapy can be performed by expressing in T cells the genes encoding a T cell receptor (TCR) reactive against a tumor-associated antigen. This Project takes this approach, which is explored in Project 1, further by examining whether administration of hematopoietic stem cells (HSC) transduced with the genes encoding an anti-tumor TCR can lead to de novo production of T cells expressing the introduced TCR genes.. Theoretically, transduced HSC could serve as an additional long-term source of engineered T cells for sustained anti-tumor activity, to augment that of transduced mature T cells. We will develop and perform a Phase I clinical trial to assess the safety and feasibility of administering autologous CD34+ HSC transduced to express a TCR recognizing a peptide from MART-1 for immunotherapy of patients with advanced melanoma. These engineered CD34+ cells will be co-administered along with mature T cells transduced to express the same MART-1 TCR, but with a distinguishable reporter gene. This dual marking approach will allow identification, isolation and characterization of the TCR-expressing T cells produced in vivo from the CD34+ cells and determination of their in vivo biodistribution by using PET imaging. During the planning stage of the clinical trial, we will use pre-clinical models of human T cell production from HSC to perform detailed characterization of the T cells derived from transduced human HSC. Ongoing scientific collaborations will occur with all of the Projects and Cores of this Program. The clinical trial of this Project 3 will be performed in years 4-5 of this program, building on the clinical trial of Project 1 that defines the optimal methods for administration of the TCR-transduced T cells. These studies will assess the potential role of HSC for cancer immunotherapy using TCR-based approaches.

Public Health Relevance

Benefit to public health: Immunotherapy is emerging as a new modality to treat cancer, with the prospect for novel effective therapies and safer outcomes for affected patients. It is possible to engineer the human immune system to eradicate malignant cells by expressing T cell receptors against tumor-associated antigens and one promising approach is to use hematopoietic stem cells (HSC) as the source of these tumor-targeted T cells. This Project will explore the safety and feasibility of the use of HSC for immunotherapy of cancer and may lead to improved cancer therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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California Institute of Technology
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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

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