title: Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic 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.
authors: Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at the University of California, Los Angeles CA 90095, USA. dvatakis@ucla.edu
authors: Dimitrios N
authors: DN
authors: Vatakis
authors: Richard C
authors: RC
authors: Koya
authors: Christopher C
authors: CC
authors: Nixon
authors: Liu
authors: L
authors: Wei
authors: Sohn G
authors: SG
authors: Kim
authors: Patricia
authors: P
authors: Avancena
authors: Gregory
authors: G
authors: Bristol
authors: David
authors: D
authors: Baltimore
authors: Donald B
authors: DB
authors: Kohn
authors: Antoni
authors: A
authors: Ribas
authors: Caius G
authors: CG
authors: Radu
authors: Zoran
authors: Z
authors: Galic
authors: Jerome A
authors: JA
authors: Zack
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D045744:Cell Line, Tumor; D005434:Flow Cytometry / Q000379:methods; D005818:Genetic Engineering / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology; D051379:Mice; D016513:Mice, SCID; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D013234:Stem Cells / Q000166:cytology; D013950:Thymus Gland / Q000378:metabolism; D019076:Transgenes
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents