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US 12,758,614 B2Granted
Augmenting antigen-negative cell death in antigen-targeted immunotherapies
AssigneeFred Hutchinson Cancer Center
InventorsCameron J. Turtle, Salvatore Fiorenza
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Abstract
Combination therapies that include (i) an immune cell that expresses a chimeric antigen receptor (CAR) or similar molecule and (ii) a compound that preserves or potentiates the in vivo actions of tumor necrosis factor alpha (TNFα) against cancer cells are described. The combination therapies result in the killing of antigen-negative cells in the vicinity of immunotherapy targeted-antigen-positive cells reducing the survivability of escape variants and providing other benefits.
Claims20
An immune cell genetically modified to express:
- (i) a first molecule comprising a chimeric antigen receptor (CAR) comprising an extracellular component linked to an intracellular component by a transmembrane domain, wherein the extracellular component comprises a binding domain that binds an antigen expressed by a cancer cell and wherein the intracellular component comprises an effector domain;
- and
- (ii) a second molecule comprising a tumor necrosis factor alpha (TNFα) signal potentiator comprising tumor necrosis factor-like weak inducer of apoptosis (TWEAK);
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL);
- or
- tumor necrosis factor superfamily member 14 (LIGHT).
3 more elements
A system comprising:
- (i) a first nucleic acid encoding a chimeric antigen receptor (CAR), that when expressed by a cell, comprises an extracellular component linked to an intracellular component by a transmembrane domain, wherein the extracellular component comprises a binding domain that binds an antigen expressed by a cancer cell and wherein the intracellular component comprises an effector domain;
- and
- (ii) (a) a second nucleic acid encoding a tumor necrosis factor alpha (TNFα) signal potentiator comprising:
- tumor necrosis factor-like weak inducer of apoptosis (TWEAK);
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL);
- or
- tumor necrosis factor superfamily member 14 (LIGHT);
- or
- (b) a small molecule TNFα signal potentiator selected from the group consisting of BV-6, CUDC-427, GDC-0152, LCL161, Rocaglamide, Escin, Emricasan, Birinapant, ASTX660, AZD5582, BI 891065, DEBIO 1143, APG-1387, HGS1029, and AEG35156.
6 more elements
Dependencies are inferred from the claim text.