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.
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.
|Liu, Yarong; Xiao, Liang; Joo, Kye-Il et al. (2014) In situ modulation of dendritic cells by injectable thermosensitive hydrogels for cancer vaccines in mice. Biomacromolecules 15:3836-45|
|Javed, Muhammad Rashed; Chen, Supin; Kim, Hee-Kwon et al. (2014) Efficient radiosynthesis of 3'-deoxy-3'-18F-fluorothymidine using electrowetting-on-dielectric digital microfluidic chip. J Nucl Med 55:321-8|
|Liu, Yarong; Fang, Jinxu; Joo, Kye-Il et al. (2014) Codelivery of chemotherapeutics via crosslinked multilamellar liposomal vesicles to overcome multidrug resistance in tumor. PLoS One 9:e110611|
|Gschweng, Eric H; McCracken, Melissa N; Kaufman, Michael L et al. (2014) HSV-sr39TK positron emission tomography and suicide gene elimination of human hematopoietic stem cells and their progeny in humanized mice. Cancer Res 74:5173-83|
|Liu, Yarong; Fang, Jinxu; Kim, Yu-Jeong et al. (2014) Codelivery of doxorubicin and paclitaxel by cross-linked multilamellar liposome enables synergistic antitumor activity. Mol Pharm 11:1651-61|
|Chodon, Thinle; Comin-Anduix, Begoña; Chmielowski, Bartosz et al. (2014) Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin Cancer Res 20:2457-65|
|Ribas, Antoni; Tumeh, Paul C (2014) The future of cancer therapy: selecting patients likely to respond to PD1/L1 blockade. Clin Cancer Res 20:4982-4|
|Gschweng, Eric; De Oliveira, Satiro; Kohn, Donald B (2014) Hematopoietic stem cells for cancer immunotherapy. Immunol Rev 257:237-49|
|Liu, Yarong; Joo, Kye-Il; Lei, Yuning et al. (2014) Visualization of intracellular pathways of engineered baculovirus in mammalian cells. Virus Res 181:81-91|
|Atefi, Mohammad; Avramis, Earl; Lassen, Amanda et al. (2014) Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. Clin Cancer Res 20:3446-57|
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