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 - Funding Information:
The first author would like to thank Dr. Idit Shub, Gal Tsachor and Ilan Edelson for there long lasting support and endless belief. This work was supported by the Israel Science Foundation grant 2484/19 (A.P.), the US/Israel Binational Science Foundation grant 2019337 (A.P.), the joint NRF (Singapore)-ISF grant 3127/19 (A.P.), the Ministry of Health grant 3/15080 (R.G. and A.P.), the NIBN-CARTIV grant. and the DKFZ-MOST 3-14370. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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 -
