Chimeric antigen receptor mediated cell targeting
Inventors
Conway, Anthony • Jain, Sumiti • Lee, Gary K. • Reik, Andreas • Truong, Lynn N.
Assignees
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Publication Number
US-12516098-B2
Publication Date
2026-01-06
Expiration Date
Abstract
Disclosed herein are methods and compositions for engineering cells to express a CAR where the cells also have inactivated TCR, HPRT, PD1, CISH and/or HLA genes, using engineered nucleases comprising at least one DNA binding domain and a cleavage domain or cleavage half-domain in conditions able to preserve cell viability. Polynucleotides encoding nucleases, vectors comprising polynucleotides encoding nucleases and cells comprising polynucleotides encoding nucleases and/or cells comprising nucleases are also provided.
Core Innovation
The disclosure describes an isolated population of genetically modified T cells expressing a chimeric antigen receptor and a fusion protein comprising beta-2-microglobulin with HLA-E and/or HLA-G. The polynucleotides encoding the CAR and fusion protein are linked by a self-cleaving peptide and integrated into TTGAAA of exon c2 of the T-cell receptor-alpha gene. The description reports targeted integration, CAR expression, and antigen-specific killing of CD19-positive target cells.
Modified HLA-E or HLA-G expression reduces NK-cell killing to support allogeneic adoptive cell therapy and universal-donor CAR-T applications. Reported evaluations demonstrate efficient TRAC and B2M disruption alongside transgene integration, detecting CAR and B2M–HLA-E or HLA-G expression with reduced endogenous B2M and HLA-ABC signals. The background section and the problem being solved are not explicitly described in the provided content.
Claims Coverage
The provided claims identify one independent claim directed to an isolated population of genetically modified T cells, characterized by three inventive features.
Genetically modified T-cell population
The independent claim covers an isolated population of T cells comprising genetically modified T cells.
Linked CAR and B2M–HLA fusion construct
At least one modified T cell comprises a vector or polynucleotides encoding a CAR linked by a self-cleaving peptide to a B2M–HLA-E and/or HLA-G fusion protein.
Targeted integration into the TCRA gene
The CAR- and fusion-protein-encoding polynucleotides are integrated into TTGAAA of exon c2 of a TCRA gene. Dependent claims further specify endogenous B2M inactivation, a P2A peptide, linker composition, an hPGK promoter, WPRE, and homology arms.
The claim coverage centers on a genetically modified T-cell population with linked CAR and B2M–HLA-E and/or HLA-G fusion protein coding sequences integrated into the specified TCRA locus, with dependent claims specifying additional cell and vector features.
Stated Advantages
The description presents modified HLA-E or HLA-G expression as a means to reduce NK-cell killing and support potential allogeneic adoptive cell therapy with reduced TCR- and HLA-mediated incompatibility.
Reported experiments show efficient TRAC and B2M disruption alongside transgene integration, with CAR expression and antigen-specific killing of CD19-positive target cells.
Documented Applications
Universal-donor CAR-T applications and potential use of the genetically modified T cells in allogeneic adoptive cell therapy.
CAR-T cells targeting CD19-positive target cells as demonstrated in reported experiments.
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