Most Adoptive Cell
Therapies (ACT), including CAR T cell therapies, suffer failure because of the severe
side effects due to loss-of-control of the therapeutic cells once they are
inside the patient’s body, suggesting that novel strategies must be developed
for a better in vivo control of these engineered cells. In the meantime, CAR T
cell therapies targeting solid tumors have not experienced the remarkable
success achieved with hematopoietic cancers, mainly due to continuous tumor
antigen exposure and a suppressive tumor microenvironment. Here we designed a
private passageway fusion receptor, which is composed of a ligand binding
domain and a glycosylphosphatidylinositol (GPI) anchoring domain, to be
expressed and localized to the surface of CAR T cells independently to the
classical CAR T construct. These ligand binding domains preserve high binding
affinity towards their cognate ligands and are only expressed on the CAR T
cells that have been transduced. Therefore, cytotoxic drugs or
immunosuppressants linked to the corresponding targeting ligands are shown to
be specifically delivered to these fusion receptor positive CAR T cells for
lowering the activity of the over-activated CAR T cells. On the other hand, we
discovered that a potent TLR7 agonist is able to enhance the lysis effect of
the exhausted CAR T cells in a co-culture model. Serial releasable and
non-releasable targeted TLR7 agonists were prepared and tested. Based on these
data, we suggest that our secret passageway fusion receptor platform provides a
better control of the activity of CAR T cells using the corresponding targeting
ligand-payload conjugates in a dose dependent manner and function as a doorway
for the delivery of instructions to CAR T cells for versatile purposes.
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/8968502 |
| Date | 16 December 2020 |
| Creators | Boning Zhang (7011482) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/DESIGN_OF_A_PRIVATE_PASSAGEWAY_FUSION_RECEPTOR_FOR_SENSITIVE_CONTROL_OF_ADOPTIVE_CELL_THERAPIES/8968502 |
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