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

作者：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

来源：Proceedings of the National Academy of Sciences, 2011, 108(51): E1408-E1416.

DOI：10.1073/pnas.1115050108

• stem cell therapy
• hematopoietic progenitors
• T-cell engineering
• tumor immunotherapy
• BLT mice

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 naive CD(8+) T-cell population. Following tumor challenge, these transgenic CD(8+) 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.

• 出版日期2011-12-20