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

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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Aurora: a new direction for a new dawn

Blood ◽

10.1182/blood-2011-11-389452 ◽

2012 ◽

Vol 119 (2) ◽

pp. 322-323

Author(s):

Katayoun Rezvani

Keyword(s):

T Cell Receptor ◽

Aurora Kinase ◽

Cell Receptor ◽

Genetically Engineered ◽

Target Antigen ◽

Adoptive Therapy ◽

Aurora Kinase A ◽

Large Numbers ◽

Kinase A ◽

Gene Transfer Techniques

The use of gene transfer techniques to introduce TCR α/β genes that confer specificity for a target antigen offers the opportunity to produce large numbers of cancer-specific T cells for adoptive therapy.1 In this issue of Blood, Nagai and colleagues examine the feasibility of adoptive therapy using lymphocytes genetically engineered to express the T-cell receptor (TCR) for the leukemia-associated antigen Aurora kinase A (AURKA).2

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Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy

Biochemical Society Transactions ◽

10.1042/bst20150291 ◽

2016 ◽

Vol 44 (2) ◽

pp. 412-418 ◽

Cited By ~ 79

Author(s):

Oladapo O. Yeku ◽

Renier J. Brentjens

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Second Generation ◽

Cell Receptor ◽

Tumour Microenvironment ◽

Interleukin 12 ◽

Car T Cells ◽

Car T Cell ◽

Car T

Chimaeric antigen receptor (CAR) T-cells are T-cells that have been genetically modified to express an artificial construct consisting of a synthetic T-cell receptor (TCR) targeted to a predetermined antigen expressed on a tumour. Coupling the T-cell receptor to a CD3ζ signalling domain paved the way for first generation CAR T-cells that were efficacious against cluster of differentiation (CD)19-expressing B-cell malignancies. Optimization with additional signalling domains such as CD28 or 4-1BB in addition to CD3ζ provided T-cell activation signal 2 and further improved the efficacy and persistence of these second generation CAR T-cells. Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported. In this review, we discuss a different approach to optimization of CAR T-cells. Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence. The choice of the ‘armor’ agent is based on knowledge of the tumour microenvironment and the roles of other elements of the innate and adaptive immune system. Although there are several variants of armored CAR T-cells under investigation, here we focus on three unique approaches using interleukin-12 (IL-12), CD40L and 4-1BBL. These agents have been shown to further enhance CAR T-cell efficacy and persistence in the face of a hostile tumour microenvironment via different mechanisms.

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