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Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells

Author:
Vatakis, Dimitrios N., Koya, Richard C., Nixon, Christopher C., Wei, Liu, Kim, Sohn G., Avancena, Patricia, Bristol, Gregory, Baltimore, David, Kohn, Donald B., Ribas, Antoni, Radu, Caius G., Galic, Zoran, Zack, Jerome A.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2011 v.108 no.51 pp. E1408
ISSN:
0027-8424
Subject:
CD8-positive T-lymphocytes, anticarcinogenic activity, bone marrow, gene therapy, humans, immune response, immunotherapy, melanoma, mice, models, receptors, stem cells
Abstract:
The goal of cancer immunotherapy is the generation of an effective, stable, and self-renewing antitumor T-cell population. One such approach involves the use of high-affinity cancer-specific T-cell receptors in gene-therapy protocols. Here, we present the generation of functional tumor-specific human T cells in vivo from genetically modified human hematopoietic stem cells (hHSC) using a human/mouse chimera model. Transduced hHSC expressing an HLA-A*0201–restricted melanoma-specific T-cell receptor were introduced into humanized mice, resulting in the generation of a sizeable melanoma-specific naïve CD8+ T-cell population. Following tumor challenge, these transgenic CD8+ T cells, in the absence of additional manipulation, limited and cleared human melanoma tumors in vivo. Furthermore, the genetically enhanced T cells underwent proper thymic selection, because we did not observe any responses against non–HLA-matched tumors, and no killing of any kind occurred in the absence of a human thymus. Finally, the transduced hHSC established long-term bone marrow engraftment. These studies present a potential therapeutic approach and an important tool to understand better and to optimize the human immune response to melanoma and, potentially, to other types of cancer.
Agid:
211593