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

Authors: Yeku, O. O.; Brentjens, R. J.
Article Title: Armored CAR T-cells: Utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy
Abstract: 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. ©2016 Authors; published by Portland Press Limited.
Keywords: adoptive immunotherapy; chimaeric antigen receptor; armored chimaeric antigen receptor t-cell (car t-cell)
Journal Title: Biochemical Society Transactions
Volume: 44
Issue: 2
ISSN: 0300-5127
Publisher: Portland Press Ltd  
Date Published: 2016-04-01
Start Page: 412
End Page: 418
Language: English
DOI: 10.1042/bst20150291
PROVIDER: scopus
PUBMED: 27068948
PMCID: PMC5529098
Notes: Review -- Export Date: 2 February 2017 -- Source: Scopus
Citation Impact
MSK Authors
  1. Renier J Brentjens
    267 Brentjens
  2. Oladapo Olumoroti Yeku
    16 Yeku