Chimeric antigen receptor t cell compositions
Assigneebluebird bio, Inc.
InventorsMichael T. CERTO, Wai-Hang LEUNG
Life of this patent
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Abstract
The invention provides improved compositions for adoptive immune effector cell therapies for treatment, prevention, or amelioration of numerous conditions including, but not limited to cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency.
Claims80
A chimeric antigen receptor (CAR) T cell, comprising, one or more modified T cell receptor alpha (TCRα) alleles, wherein the CAR T cell secretes an increased amount of proinflammatory cytokines when bound to a target antigen compared to a CAR T cell bound to the target antigen that lacks one or more modified TCRα alleles.
A CAR T cell, comprising:
- a) one or more modified TCRα alleles;
- and
- b) a nucleic acid encoding a CAR that binds a target antigen,
- wherein the CAR T cell secretes an increased amount of one or more proinflammatory cytokines when contacted with a target cell expressing the target antigen compared to a CAR T cell bound to the target antigen that lacks one or more modified TCRα alleles.
A CAR T cell, comprising:
- a) one or more modified TCRα alleles;
- and
- b) one or more proviral integrants comprising a nucleic acid encoding a CAR that binds a target antigen,
- wherein the CAR T cell secretes an increased amount of one or more proinflammatory cytokines when bound to a target antigen compared to a CAR T cell bound to the target antigen that lacks one or more modified TCRα alleles.
A CAR T cell, comprising, one or more modified TCRα alleles, wherein a donor repair template comprising a nucleic acid encoding a CAR that binds a target antigen is inserted into the one or more TCRα alleles by homology directed repair, and wherein the CAR T cell secretes an increased amount of one or more proinflammatory cytokines when bound to a target antigen compared to a CAR T cell bound to the target antigen that lacks one or more modified TCRα alleles.
A method of making a CAR T cell comprising:
- a) engineering a double-strand break at a target site in a TCRα allele, wherein the break is repaired by non-homologous end joining (NHEJ), thereby generating a modified TCRα allele;
- and
- b) transducing the T cell with a viral vector encoding a CAR;
- wherein the CAR T cell secretes an increased amount of one or more proinflammatory cytokines when bound to a target antigen compared to a CAR T cell bound to the target antigen that lacks a modified TCRα allele.
A method of making a CAR T cell comprising:
- a) engineering a double-strand break at a target site in a TCRα allele;
- and
- b) transducing the T cell with a viral vector comprising a donor repair template that comprises an RNA polymerase II promoter operably linked to a nucleic acid encoding a CAR;
- wherein the donor repair template is incorporated into the TCRα allele by homology directed repair at the site of the double-strand break (DSB);
- and
- wherein the CAR T cell secretes an increased amount of one or more proinflammatory cytokines when bound to a target antigen compared to a CAR T cell bound to the target antigen that lacks a modified TCRα allele.
A method of increasing the efficacy of a CAR T cell comprising decreasing the availability of TCRα signaling components on the CAR T cell surface by introducing an engineered nuclease that creates a double-strand break (DSB) at a target site in a TCRα allele to modify the TCRα allele.
Dependencies are inferred from the claim text.