Altering gene expression in modified T cells and uses thereof
AssigneeThe Trustees of the University of Pennsylvania
InventorsYangbing Zhao, Jiangtao Ren, Xiaojun Liu, Carl H. June
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Abstract
The present invention relates to compositions and methods for generating a modified T cell with a nucleic acid capable of downregulating endogenous gene expression selected from the group consisting of TCR α chain, TCR β chain, beta-2 microglobulin and FAS further comprising a nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a surface antigen on a target cell or an electroporated nucleic acid encoding a chimeric antigen receptor (CAR). Also included are methods and pharmaceutical compositions comprising the modified T cell for adoptive therapy and treating a condition, such as an autoimmune disease.
Claims15
A method for stimulating a T cell-mediated immune response to a target cell or tissue in a subject comprising:
- (i) administering to the subject an effective amount of a pharmaceutical composition comprising a CRISPR-modified T cell, wherein the CRISPR-modified T cell comprises:
- (a) a CRISPR-mediated insertion or deletion in an endogenous TCR a chain (TRAC) gene locus capable of downregulating gene expression of the endogenous TCR a chain gene, wherein the CRISPR-mediated insertion or deletion is within a TCR a chain nucleotide sequence comprising SEQ ID NO:
- 1;
- (b) a CRISPR-mediated insertion or deletion in an endogenous TCR β chain (TRBC) gene locus capable of downregulating gene expression of the endogenous TCR B chain gene;
- (c) a CRISPR-mediated insertion or deletion in an endogenous beta-2-microglobulin (B2M) gene locus capable of downregulating gene expression of the endogenous B2M gene, wherein the CRISPR-mediated insertion or deletion is within a B2M nucleotide sequence comprising SEQ ID NO:
- 3, 44, 77, or 78;
- and
- (d) a nucleic acid encoding an exogenous T cell receptor (TCR) comprising affinity for a tumor associated antigen (TAA) on the target cell or tissue;
- and
- (ii) inducing lysis of the target cell or tissue by administering to the subject an effective amount of a pharmaceutical composition comprising an antibody that selectively blocks CTLA-4, PD-1 and/or PD-L1.
A method for stimulating a T cell-mediated immune response to a target cell or tissue in a subject comprising administering to the subject an effective amount of a pharmaceutical composition comprising a CRISPR-modified T cell, and a pharmaceutical composition comprising an antibody that selectively blocks CTLA-4, PD-1 and/or PD-L1;
- wherein the CRISPR-modified T cell comprises:
- (a) a CRISPR-mediated insertion or deletion in an endogenous TCR α chain (TRAC) gene locus capable of downregulating gene expression of the endogenous TCR α chain gene, wherein the CRISPR-mediated insertion or deletion is in a TCR α chain nucleotide sequence comprising SEQ ID NO:
- 1;
- (b) a CRISPR-mediated insertion or deletion in an endogenous TCR β chain (TRBC) gene locus capable of downregulating gene expression of the endogenous TCR β chain gene;
- (c) a CRISPR-mediated insertion or deletion in an endogenous B2M gene locus capable of downregulating gene expression of the B2M gene, wherein the CRISPR-mediated insertion or deletion is within a B2M nucleotide sequence comprising SEQ ID NO:
- 3, 44, 77, or 78;
- and
- (d) a nucleic acid encoding a modified NY-ESO-1 T cell receptor (TCR), wherein the modified NY-ESO-1 TCR is an 8F NY-ESO-1 TCR.
Dependencies are inferred from the claim text.