Composition and method for reducing expression of checkpoint inhibitors in t cells expressing a car or ctl
AssigneeCity of Hope
InventorsSaul J. Priceman, John C. Burnett, Yukiko Yamaguchi, Elizabeth Epps
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Abstract
Described herein is an approach for targeting multiple critical checkpoint genes involved in T cell exhaustion, for example, PD-1, TIM3, and LAG-3 in a manner that allows knock-down of their expression in T cells that also express a T cell receptor targeted to cancer cells, e.g., a CAR targeted to a cancer antigen or a T cell receptor (TCR).
Claims38
A nucleic acid vector comprising an shRNA sequence targeted to an mRNA encoding a checkpoint inhibitor selected from the group consisting of PD-1, TIM3 and LAG3 and a nucleic acid sequence encoding a chimeric antigen receptor (CAR).
A nucleic acid vector comprising an H1 DNA POL III promoter, an U6 DNA POL III promoter, and a 75K DNA POL III promoter, where each promoter is operably linked to an shRNA nucleic acid sequence targeted to an mRNA encoding a checkpoint inhibitor.
The nucleic acid vector of claim 44, wherein the CAR comprises, from amino to carboxy terminus:
- a targeting domain for targeting an antigen;
- a spacer domain;
- a transmembrane domain;
- a co-stimulatory domain;
- and a CD3ζ signaling domain.
Dependencies are inferred from the claim text.