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-12280111-B2
Publication Date
2025-04-22
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 document describes modified human tumor infiltrating lymphocytes (TILs) for treating cancer in a subject. The modified TILs comprise an insertion, deletion, or mutation in an endogenous SOCS1 gene, and endogenous SOCS1 gene expression is reduced relative to unmodified human TILs obtained from the subject.
A gene-regulating system is described as reducing gene expression and/or function in immune effector cells. The disclosure includes gene editing or nucleic-acid- or protein-based gene-regulation approaches, including RNA interference, antisense RNA, morpholinos, CRISPR/Cas with gRNA/PAM specificity, zinc-finger systems, TALEN, and combinations of nucleic-acid and protein approaches.
The disclosed compositions may further include exogenous antigen-specific receptors and/or exogenous transgenes, including immune-activating molecules, detectable tags, and safety switches. The document also states that use is applicable broadly for cancers and solid tumors, including settings described as PD-1/PD-L1-insensitive or -resistant.
Claims Coverage
Two independent claims are identified. The claims center on modified human TILs with an insertion, deletion, or mutation in an endogenous SOCS1 gene and reduced endogenous SOCS1 gene expression relative to unmodified subject-derived TILs, with one claim further requiring selection of a subject whose solid tumor is insensitive to, or resistant to, treatment with an immune checkpoint inhibitor and a stated administration range.
SOCS1-modified tumor infiltrating lymphocytes for cancer treatment
Administering a composition comprising a therapeutically effective amount of modified human tumor infiltrating lymphocytes (TILs) that comprise an insertion, deletion, or mutation in an endogenous SOCS1 gene, wherein endogenous SOCS1 gene expression is reduced in the modified human TILs relative to unmodified human TILs obtained from the subject.
Immune checkpoint inhibitor-insensitive or resistant solid tumor selection with SOCS1-modified TIL administration
Selecting a subject who has a solid tumor that is insensitive to, or resistant to, treatment with an immune checkpoint inhibitor, and administering a composition comprising about 1×10^7 and about 1×10^12 modified human tumor infiltrating lymphocytes (TILs) that comprise an insertion, deletion, or mutation in an endogenous SOCS1 gene, wherein endogenous SOCS1 gene expression is reduced in the modified human TILs relative to unmodified human TILs obtained from the subject.
The independent claims define treatment of cancer using modified human TILs carrying an insertion, deletion, or mutation in an endogenous SOCS1 gene, with reduced SOCS1 gene expression compared to unmodified subject-derived TILs; the solid-tumor claim adds selection for immune checkpoint inhibitor insensitivity or resistance and a stated TIL amount range.
Stated Advantages
enhanced effector functions, including increased proliferation, tumor infiltration, persistence, cytotoxicity, pro-inflammatory cytokine production, and resistance to exhaustion.
Documented Applications
Treatment of cancer in a subject using modified human tumor infiltrating lymphocytes (TILs) with reduced endogenous SOCS1 gene expression.
Treatment of a solid tumor in a subject whose solid tumor is insensitive to, or resistant to, treatment with an immune checkpoint inhibitor, using SOCS1-edited modified human TILs.
Treatment settings described as PD-1/PD-L1-insensitive or -resistant.
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