Clinical application of adoptive transfer of TCR-engineered CTLs, a promising cancer immunotherapy, is limited by difficulties in obtaining sufficient numbers of effective CTLs and by TCR subunit misparing in engineered CTLs. As we reported at the 2012 AAI Meeting, humanized mice, made by transplantation of thymic tissue and CD34+ cells that were transduced with HLA-A2-restricted melanoma antigen (MART-1)-specific TCR, showed efficient development of MART-1-TCR+ human T cells expressing only the engineered TCR. Here we show that although T cells expressing MART-1-TCR were mainly CD8+, CD4 T cells expressing MART-1-TCR were also detected in most humanized mice examined. However, only MART-1-TCR+CD8+ T cells showed specific responses to MART-1 peptide immunization in vivo. In vitro CTL assay revealed that MART-1-TCR+CD8+ cells from humanized mice can mediate robust specific killing of melanoma cells, and fully retain their cytotoxicity after substantial in vitro expansion (up to tens of thousands of times). Adoptive transfer of these expanded CD8 T cells induced potent antitumor responses in both subcutaneous and metastatic tumor models. Furthermore, treatment with IL-15 significantly improved the survival and anti-tumor effects of adoptively transferred MART-1-TCR+CD8+ cells. These findings indicate that humanized mice provide not only an in vivo model for preclinical research, but also a potential means of producing a large quantity of human T cells for cancer immunotherapy.
- Copyright © 2013 by The American Association of Immunologists, Inc.