sb8b00512_si_001.pdf (1.7 MB)
Inducible Gene Switches with Memory in Human T Cells for Cellular Immunotherapy
journal contribution
posted on 2019-07-03, 00:00 authored by Deboki Chakravarti, Leidy D. Caraballo, Benjamin H. Weinberg, Wilson W. WongCell-based therapies that employ
engineered T cellsincluding
those modified to express chimeric antigen receptors (CARs)to
target cancer cells have demonstrated promising responses in clinical
trials. However, engineered T cell responses must be regulated to
prevent severe side effects such as cytokine storms and off-target
responses. Here we present a class of recombinase-based gene circuits
that will enable inducible, one-time state switching in adoptive T
cell therapy using an FDA-approved drug, creating a generalizable
platform that can be used to control when and how strongly a gene
is expressed. These circuits exhibit memory such that induced T cells
will maintain any changes made even when the drug inducer is removed.
This memory feature avoids prolonged drug inducer exposure, thus reducing
the complexity and potential side effect associated with the drug
inducer. We have utilized these circuits to control the expression
of an anti-Her2-CAR, demonstrating the ability of these circuits to
regulate CAR expression and T cell activity. We envision this platform
can be extended to regulate other genes involved in T cell behavior
for applications in various adoptive T cell therapies.