Cited by 2Open Access
Southwestern Medical Center
ORCID: 0009-0000-1470-1324Publishes on CAR-T cell therapy research, Monoclonal and Polyclonal Antibodies Research, Cutaneous lymphoproliferative disorders research. 20 papers and 3 citations.
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Antibody-based therapies have revolutionized cancer treatment but have several limitations. These include downregulation of the target antigen, mutation of the target epitope, and, in the case of antibody-drug conjugates (ADC), resistance to the chemotherapy warhead. As TROP2-targeted therapy with ADCs yields responses in TROP2+ solid tumors, but the responses lack the durability observed with other immunotherapy-based approaches, we developed TROP2-targeting chimeric antigen receptor (CAR) T cells as an alternative. The TROP2-directed CAR T cells showed high potency against multiple solid tumor models. Moreover, TROP2-directed CAR T-cell therapy preserved high potency in models of ADC resistance and could be further engineered to prevent cell therapy resistance. This was achieved by leveraging fully human single-domain (VH-only) binder discovery to rationally engineer dual epitope binding-based (biparatopic) CARs. This work highlights the potency of CAR T-cell therapies and how rational engineering leveraging dual-VH targeting domains can overcome resistance pathways to current therapies. In future work, the CAR engineering approaches presented here can serve as a platform to be partnered with other strategies to address the suppressive tumor microenvironment.
<p>Figure S11. In vitro live-cell imaging of PC9 WT treated with various TROP2 CAR constructs. In vitro activity in live-cell imaging assay of TROP2 CARs against PC9 WT. PC9 was transduced with GFP and live-cell imaging performed on Incucyte with counting of green objects. Cytotoxicity index is green cell object count relative to t = 0 when CARs were applied at E:T of 0.25:1. Data are representative of multiple independent experiments with different donors.</p>
<p>Figure S12. In vivo kinetics of CAR infiltration into PC9 subcutaneous tumor. PC9 tumors once established at ∼100 mm3 were injected with either 2.5E6 irrelevantly targeted control or TROP2 CAR+ cells expressing NanoLuciferase, which allows for in vivo tracking of CAR. Mice were imaged after injecting with FFz substrate at indicated time points post CAR engraftment, with right flank representing PC9 mCRD and left flank PC9 mCPD tumor inoculation site.</p>
<p>Amino-acid sequences of components of plasmid constructs</p>