Compositions and methods for generating a persisting population of T cells useful for the treatment of cancer
AssigneeThe Trustees of the University of Pennsylvania
InventorsMatthew J. Frigault, Yangbing Zhao, John Scholler, Carl H. June
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Abstract
The present invention provides compositions and methods for generating a genetically modified T cells comprising a chimeric antigen receptor (CAR) having an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the T cell exhibits prolonged exponential expansion in culture that is ligand independent and independent of the addition of exogenous cytokines or feeder cells.
Claims22
A lentiviral vector comprising a nucleic acid sequence encoding a continuous chimeric antigen receptor (CAR),
- (a) wherein the CAR comprises:
- (i) an anti-mesothelin antigen binding domain, a hinge domain, a transmembrane domain, a CD28 costimulatory signaling region, and a CD3 zeta signaling domain, or
- (ii) an anti-c-Met antigen binding domain, an IgG4 hinge domain, a CD28 transmembrane domain, a CD28 costimulatory signaling region, and a CD3 zeta signaling domain:
- (b) wherein the nucleic acid sequence encoding the CAR is operably linked to an elongation Growth Factor-1α (EF-1α) promoter, and
- (c) wherein, when the lentiviral vector is transduced into a T cell, the CAR contributes to constitutive secretion of IL-2 and increased proliferation of the transduced T cell in the absence of ligand, exogenous cytokine or feeder cells as compared to an untransduced T cell.
A T cell comprising a lentiviral vector comprising a nucleic acid sequence encoding a continuous chimeric antigen receptor (CAR), wherein:
- (a) the CAR comprises:
- (i) an anti-mesothelin antigen binding domain, a hinge domain, a transmembrane domain, a CD28 costimulatory signaling region, and a CD3 zeta signaling domain, or
- (ii) an anti-c-Met antigen binding domain, an IgG4 hinge domain, a CD28 transmembrane domain, a CD28 costimulatory signaling region, and a CD3 zeta signaling domain;
- (b) the nucleic acid sequence encoding the CAR is operably linked to an elongation Growth Factor-1α (EF-1α) promoter, and
- (c) when the lentiviral vector is transduced into a T cell, the CAR contributes to constitutive secretion of IL-2 and increased proliferation of the transduced T cell in the absence of ligand, exogenous cytokine or feeder cells as compared to an untransduced T cell.
A persisting population of genetically modified T cells, wherein the T cells comprise a lentiviral vector comprising a nucleic acid sequence encoding a continuous chimeric antigen receptor (CAR), wherein:
- (a) the CAR comprises:
- (i) an anti-mesothelin antigen binding domain, a hinge domain, a transmembrane domain, a CD28 costimulatory signaling region, and a CD3 zeta signaling domain, or
- (ii) an anti-c-Met antigen binding domain, an IgG4 hinge domain, a CD28 transmembrane domain, a CD28 costimulatory signaling region, and a CD3 zeta signaling domain;
- (b) the nucleic acid sequence encoding the CAR is operably linked to an elongation Growth Factor-1α (EF-1α) promoter, and
- (c) when the lentiviral vector is transduced into a T cell, the CAR contributes to constitutive secretion of IL-2 and increased proliferation of the transduced T cell in the absence of ligand, exogenous cytokine or feeder cells as compared to an untransduced T cell.
Dependencies are inferred from the claim text.