Gene-regulating compositions and methods for improved immunotherapy
Inventors
Benson, Micah • Merkin, Jason J. • Kryukov, Gregory V. • Shenker, Solomon Martin • Schlabach, Michael R. • Tubo, Noah Jacob • Kaberna, II, James Martin
Assignees
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Publication Number
US-12123021-B2
Publication Date
2024-10-22
Expiration Date
Abstract
The present disclosure provides methods and compositions related to the modification of immune effector cells to increase therapeutic efficacy. In some embodiments, immune effector cells modified to reduce expression of one or more endogenous target genes, or to reduce one or more functions of an endogenous protein to enhance effector functions of the immune cells are provided. In some embodiments, immune effector cells further modified by introduction of transgenes conferring antigen specificity, such as exogenous T cell receptors (TCRs) or chimeric antigen receptors (CARs) are provided. Methods of treating a cell proliferative disorder, such as a cancer, using the modified immune effector cells described herein are also provided.
Core Innovation
The invention provides a modified human tumor-infiltrating lymphocyte (TIL) that includes an insertion, a deletion, or a mutation in an endogenous SOCS1 gene, wherein endogenous SOCS1 gene expression and/or function is reduced relative to endogenous SOCS1 gene expression and/or function in an unmodified human TIL. The modified TIL is described as having increased anti-tumor efficacy relative to anti-tumor efficacy of an unmodified human TIL.
The disclosure further defines gene-regulating systems for targeting SOCS1, including one or more gRNAs and a Cas endonuclease, where the gRNA targeting domain sequence binds to a target nucleic acid sequence in an endogenous SOCS1 gene. It also describes CRISPR gene-regulating systems by targeting specificity of gRNA targeting domains, including sequence identity thresholds, target sequences defined by genomic coordinate tables and enumerated SEQ ID NOs, and measures intended to reduce off-target binding and innate immune activation.
The invention additionally includes additional endogenous gene edits in immune-relevant genes and immune activating molecules. The modified human TIL may include an insertion, a deletion, or a mutation in an endogenous gene selected from a specified list, and may include an immune activating molecule chosen from cytokines, chemokines, co-stimulatory molecules, activating peptides, or antibodies/antigen-binding fragments.
Claims Coverage
The consolidated claim coverage centers on one inventive concept: a modified human TIL with reduced endogenous SOCS1 gene expression and/or function and increased anti-tumor efficacy, implemented through SOCS1 locus modification. The claim set also includes dependent features for gRNAs and a Cas endonuclease, additional endogenous gene edits, and immune activating molecules.
Modified human TIL with reduced endogenous SOCS1 and increased anti-tumor efficacy
A modified human tumor-infiltrating lymphocyte (TIL) comprising an insertion, a deletion, or a mutation in an endogenous SOCS1 gene, wherein endogenous SOCS1 gene expression and/or function is reduced relative to endogenous SOCS1 gene expression and/or function in an unmodified human TIL, and wherein anti-tumor efficacy of the modified human TIL is increased relative to anti-tumor efficacy of an unmodified human TIL.
TIL including one or more gRNAs and a Cas endonuclease
The modified human TIL further includes one or more gRNA and a Cas endonuclease.
Gene-regulating system with gRNA targeting an endogenous SOCS1 sequence
A gene-regulating system includes one or more gRNAs and a Cas endonuclease, where the gRNA targeting domain sequence binds to a target nucleic acid sequence in an endogenous SOCS1 gene.
Cas endonuclease comprising a wild-type Cas protein with two enzymatically active domains
The Cas endonuclease includes a wild-type Cas protein with two enzymatically active domains.
Additional endogenous gene edits from a specified set
The modified human TIL additionally includes an insertion, a deletion, or a mutation in an endogenous gene selected from a specified list of genes, including ANKRD11 and other immune-relevant genes.
Immune activating molecule selected from specified categories
The modified human TIL includes an immune activating molecule chosen from cytokines, chemokines, co-stimulatory molecules, activating peptides, or antibodies/antigen-binding fragments.
The claims collectively cover SOCS1 reduction in a modified human TIL to increase anti-tumor efficacy, with additional limitations directed to gRNA/Cas-based gene-regulating components, further endogenous gene edits, and immune activating molecules.
Stated Advantages
Increased anti-tumor efficacy relative to an unmodified human TIL.
Reduction of endogenous SOCS1 gene expression and/or function relative to an unmodified human TIL.
Documented Applications
Therapeutic methods for treating cancers and other disorders using the modified immune effector cells, including modified TILs, optionally with engineered immune receptors and immune activating transgenes.
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