Title | Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Vatakis DN, Koya RC, Nixon CC, Wei L, Kim SG, Avancena P, Bristol G, Baltimore D, Kohn DB, Ribas A, Radu CG, Galic Z, Zack JA |
Journal | Proc Natl Acad Sci U S A |
Volume | 108 |
Issue | 51 |
Pagination | E1408-16 |
Date Published | 2011 Dec 20 |
ISSN | 1091-6490 |
Keywords | Animals, Antigens, CD34, Antineoplastic Agents, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Flow Cytometry, Genetic Engineering, Hematopoietic Stem Cells, Humans, Immunotherapy, Lymphocytes, Tumor-Infiltrating, Mice, Mice, SCID, Models, Genetic, Neoplasm Transplantation, Stem Cells, Thymus Gland, Transgenes |
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. |
DOI | 10.1073/pnas.1115050108 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 22123951 |
PubMed Central ID | PMC3251070 |
Grant List | P01 CA132681 / CA / NCI NIH HHS / United States P30 AI028697 / AI / NIAID NIH HHS / United States P50 CA086306 / CA / NCI NIH HHS / United States AI028697 / AI / NIAID NIH HHS / United States |
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