Aurora kinase A-specific T-cell receptor gene transfer redirects T lymphocytes to display effective antileukemia reactivity

Abstract Aurora kinase A (AURKA) is overexpressed in leukemias. Previously, we demonstrated that AURKA-specific CD8+ T cells specifically and selectively lysed leukemia cells, indicating that AURKA is an excellent target for immunotherapy. In this study, we examined the feasibility of adoptive therapy using redirected T cells expressing an HLA-A*0201–restricted AURKA207-215-specific T-cell receptor (TCR). Retrovirally transduced T cells recognized relevant peptide-pulsed but not control target cells. Furthermore, TCR-redirected CD8+ T cells lysed AURKA-overexpressing human leukemic cells in an HLA-A*0201–restricted manner, but did not kill HLA-A*0201+ normal cells, including hematopoietic progenitors. In addition, AURKA207-215-specific TCR-transduced CD4+ T cells displayed target-responsive Th1 cytokine production. Finally, AURKA207-215-specific TCR-transduced CD8+ T cells displayed antileukemia efficacy in a xenograft mouse model. Collectively, these data demonstrate the feasibility of redirected T cell–based AURKA-specific immunotherapy for the treatment of human leukemia.

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A Functionally Superior Second-Generation Vector Expressing an Aurora Kinase-A-Specific T-Cell Receptor for Anti-Leukaemia Adoptive Immunotherapy

PLoS ONE ◽

10.1371/journal.pone.0156896 ◽

2016 ◽

Vol 11 (6) ◽

pp. e0156896

Author(s):

Nicholas Paul Casey ◽

Hiroshi Fujiwara ◽

Kazushi Tanimoto ◽

Sachiko Okamoto ◽

Junichi Mineno ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Adoptive Immunotherapy ◽

Second Generation ◽

Aurora Kinase ◽

Cell Receptor ◽

Aurora Kinase A ◽

Kinase A

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Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer cell receptors

Blood ◽

10.1182/blood-2004-01-0150 ◽

2004 ◽

Vol 104 (7) ◽

pp. 2116-2123 ◽

Cited By ~ 30

Author(s):

Salim Dhanji ◽

Soo-Jeet Teh ◽

Darryl Oble ◽

John J. Priatel ◽

Hung-Sia Teh

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Natural Killer ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Adaptor Protein ◽

Cell Receptor ◽

Target Cells ◽

Lymphoid Tissues

Abstract We have recently shown that interleukin-2 (IL-2)-activated CD8+CD44hi cells from normal mice express both adaptive and innate immune system receptors and specifically kill syngeneic tumor cells, particularly those that express NKG2D ligands. Here we show that CD8+ T cells from antigen-expressing H-Y T-cell receptor (TCR) transgenic mice also exhibit characteristics of both T cells and natural killer (NK) cells. Interaction with cognate self-antigen was required for the optimal expansion of these cells in peripheral lymphoid tissues. Although these cells possess a higher activation threshold relative to naive T cells, they can be activated by cytokine alone in vitro. They also undergo bystander proliferation in response to a bacterial infection in vivo. Interestingly, upon activation, the cells express the NKG2D receptor as well as the DNAX activation protein 12 (DAP12) adaptor protein. We provide evidence that NKG2D can act additively with the TCR in the killing of target cells, and it can also function as a directly activating receptor in non-major histocompatibility complex (MHC)-restricted killing of target cells. These properties of CD8+ T cells from H-Y TCR transgenic mice are remarkably similar to CD8+CD44hi cells that are found in normal mice. The H-Y TCR transgenic mice provide a well-defined system for characterizing the developmental biology and function of these cells. (Blood. 2004;104:2116-2123)

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