T cells with improved functionality
Inventors
Banerjee, Saikat • Ecker, Christopher • Shin, Yoonjung
Assignees
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Publication Number
US-12152251-B2
Publication Date
2024-11-26
Expiration Date
Abstract
Immune cell engineered to inhibit the endogenous expression of one or more of Blimp-1 and A20 and/or overexpress one or more of exogenous TCF7 and Bach2. Method of treating cancer, comprising administering the cells described herein. Method of increasing one or more of a peak fold proliferation rate, a killing efficiency, or inducing the cellular characteristics associated with naïve phenotype of an immune cell, comprising introducing an exogenous construct encoding a CAR or a TCR, and inhibiting the endogenous expression of one or more of Blimp-1 and A20, and/or introducing an exogenous construct encoding one or more of TCF7 and Bach2. Method of generating a modified immune cell, comprising introducing an exogenous construct encoding a CAR or a TCR, and inhibiting the endogenous expression of one or more of Blimp-1 and A20, and/or introducing an exogenous construct encoding one or more of TCF7 and Bach2.
Core Innovation
The invention relates to engineered T cells for cancer therapy that modulate gene expression by inhibiting endogenous Blimp-1 (PRDM1) and/or A20 (TNFAIP3) and by expressing exogenous TCF7 and exogenous Bach2. The engineered cell expresses a chimeric antigen receptor (CAR), and the exogenous Bach2 comprises an amino acid sequence at least 75% identical to the amino acid sequence set forth as SEQ ID NO: 8.
The invention further provides a method of increasing the peak fold proliferation rate of an immune cell by introducing an exogenous nucleic acid construct encoding a CAR and inhibiting endogenous expression of one or more of Blimp-1 and A20 and/or introducing an exogenous construct encoding TCF7 and Bach2. The exogenous Bach2 comprises an amino acid sequence at least 75% identical to the amino acid sequence set forth as SEQ ID NO: 8.
The document links modulation of Blimp-1, A20, TCF7, and Bach2 to engineered T-cell designs for CAR/TCR therapies. It provides mechanistic rationale based on RNAseq comparing T-cell memory subsets and reports altered expression associated with naive versus differentiated phenotypes, including TCF7, Bach2, Blimp-1, and A20.
Claims Coverage
The independent claim set centers on a modified CAR-expressing immune cell with Blimp-1 and A20 inhibition and exogenous TCF7 and Bach2 expression, and on a method of increasing peak fold proliferation rate using CAR introduction with Blimp-1 and A20 inhibition and/or TCF7 and Bach2 introduction. Across the claims, the main inventive features include the sequence constraint for exogenous Bach2 and the combined gene-expression modulation features.
Car-expressing immune cell with Blimp-1 and A20 inhibition and exogenous TCF7 and Bach2
A modified immune cell engineered to inhibit the endogenous expression of one or more of Blimp-1 and A20 and/or express exogenous TCF7 and exogenous Bach2, wherein the cell expresses a chimeric antigen receptor (CAR), and wherein the exogenous Bach2 comprises an amino acid sequence at least 75% identical to the amino acid sequence set forth as SEQ ID NO: 8.
Method of increasing peak fold proliferation rate using CAR with Blimp-1 and A20 inhibition and/or TCF7 and Bach2 introduction
A method of increasing the peak fold proliferation rate of an immune cell by introducing in the immune cell an exogenous nucleic acid construct encoding a CAR; inhibiting in the immune cell an endogenous expression of one or more of Blimp-1 and A20; and/or introducing into the immune cell an exogenous construct encoding TCF7 and Bach2, wherein the exogenous Bach2 comprises an amino acid sequence at least 75% identical to the amino acid sequence set forth as SEQ ID NO: 8.
Claim coverage centers on combining CAR expression with Blimp-1 and A20 gene modulation and exogenous expression of TCF7 and Bach2, including the sequence-identity requirement for Bach2. The method claim frames the same concept as increasing peak fold proliferation rate.
Stated Advantages
Increased peak fold proliferation rate.
Increased killing efficiency.
Increased cytokine production.
Induction of a naive phenotype.
Documented Applications
Treating cancer by administering the engineered cells.
Generating modified immune cells with the engineered properties described, including gene-expression modulation and CAR expression.
CAR/TCR therapies using engineered T cells with gene-expression modulation involving Blimp-1, A20, TCF7, and Bach2.
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