TY - JOUR
T1 - Synthetic promoters to induce immune-effectors into the tumor microenvironment
AU - Greenshpan, Yariv
AU - Sharabi, Omri
AU - Ottolenghi, Aner
AU - Cahana, Avishag
AU - Kundu, Kiran
AU - M. Yegodayev, Ksenia
AU - Elkabets, Moshe
AU - Gazit, Roi
AU - Porgador, Angel
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Harnessing the immune-system to eradicate cancer is becoming a reality in recent years. Engineered immune cells, such as chimeric antigen receptor (CAR) T cells, are facing the danger of an overt life-threatening immune response due to the ON-target OFF-tumor cytotoxicity and Cytokine Release Syndrome. We therefore developed synthetic promoters for regulation of gene expression under the control of inflammation and Hypoxia-induced signals that are associated with the tumor microenvironment (TME). We termed this methodology as chimeric-antigen-receptor-tumor-induced-vector (CARTIV). For proof of concept, we studied synthetic promoters based on promoter-responsive elements (PREs) of IFNγ, TNFα and hypoxia; triple PRE-based CARTIV promoter manifested a synergistic activity in cell-lines and potent activation in human primary T-cells. CARTIV platform can improve safety of CAR T-cells or other engineered immune-cells, providing TME-focused activity and opening a therapeutic window for many tumor-associated antigens that are also expressed by non-tumor healthy tissues.
AB - Harnessing the immune-system to eradicate cancer is becoming a reality in recent years. Engineered immune cells, such as chimeric antigen receptor (CAR) T cells, are facing the danger of an overt life-threatening immune response due to the ON-target OFF-tumor cytotoxicity and Cytokine Release Syndrome. We therefore developed synthetic promoters for regulation of gene expression under the control of inflammation and Hypoxia-induced signals that are associated with the tumor microenvironment (TME). We termed this methodology as chimeric-antigen-receptor-tumor-induced-vector (CARTIV). For proof of concept, we studied synthetic promoters based on promoter-responsive elements (PREs) of IFNγ, TNFα and hypoxia; triple PRE-based CARTIV promoter manifested a synergistic activity in cell-lines and potent activation in human primary T-cells. CARTIV platform can improve safety of CAR T-cells or other engineered immune-cells, providing TME-focused activity and opening a therapeutic window for many tumor-associated antigens that are also expressed by non-tumor healthy tissues.
UR - http://www.scopus.com/inward/record.url?scp=85100108175&partnerID=8YFLogxK
U2 - 10.1038/s42003-021-01664-7
DO - 10.1038/s42003-021-01664-7
M3 - Article
C2 - 33514819
AN - SCOPUS:85100108175
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 143
ER -
