CAR T CELL THERAPIES WITH ENHANCED EFFICACY
First Claim
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1. A cell (e.g., a population of cells) engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein expression and/or function of Tet1, Tet2 and/or Tet3 in said cell has been reduced or eliminated.
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Abstract
The invention provides compositions and methods improved CAR T cell therapies. Specifically, the invention provides cells with reduced Tet, e.g., Tet2 function or expression, and methods of use therefore. The invention further provides Tet2 inhibitors and methods of use therefore in connection with CAR T cells.
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Citations
69 Claims
- 1. A cell (e.g., a population of cells) engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein expression and/or function of Tet1, Tet2 and/or Tet3 in said cell has been reduced or eliminated.
- 46. A CAR-expressing cell therapy for use in a method of treating a subject in need thereof, the method comprising administering to said subject the CAR-expressing cell therapy and a Tet1, Tet2, and/or Tet3 inhibitor.
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53. A Tet1, Tet2 and/or Tet3 inhibitor, for use in the treatment of a subject, wherein said subject has received, is receiving, or is about to receive therapy comprising a CAR-expressing cell.
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54. A method of manufacturing a CAR-expressing cell, comprising introducing nucleic acid encoding a CAR into a cell such that said nucleic acid (or CAR-encoding portion thereof) integrates into the genome of the cell within a Tet1, Tet2 and/or Tet3 gene (e.g., within an intron or exon of a Tet1, Tet2 and/or Tet3 gene), such that Tet1, Tet2 and/or Tet3 expression and/or function is reduced or eliminated.
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55. A method of manufacturing a CAR-expressing cell, comprising contacting said CAR-expressing cell ex vivo with a Tet1, Tet2 and/or Tet3 inhibitor.
- 57. A vector comprising sequence encoding a CAR and sequence encoding a Tet inhibitor, e.g., a Tet1, Tet2, and/or Tet3 inhibitor.
- 60. A gene editing system that is specific for a sequence of a Tet gene or its regulatory elements, e.g., a Tet1, Tet2 or Tet3 gene or its regulatory elements.
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61. The gene editing system of claim 61, wherein the gene editing system is specific for a sequence of a Tet2 gene.
- 67. A composition for the ex vivo manufacture of a CAR-expressing cell, comprising a Tet inhibitor, e.g., a Tet1, Tet2, and/or Tet3 inhibitor, e.g., a Tet2 inhibitor.
Specification