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-12084682-B2
Publication Date
2024-09-10
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 is directed to a method of treating cancer in a subject in need thereof by administering a composition comprising modified human tumor infiltrating lymphocytes (TILs). The modified human TILs are modified in vitro to comprise an insertion, deletion, or mutation in an endogenous SOCS1 gene, and endogenous SOCS1 gene expression is reduced in the modified human TILs relative to unmodified human TILs obtained from the subject. The modified human TILs are autologous to the subject.
In further embodiments, the modified human TILs comprise an exogenous transgene that expresses an immune-activating molecule selected from cytokines, chemokines, co-stimulatory molecules, activating peptides, and antibodies or antigen-binding fragments. The method couples SOCS1 gene expression reduction in autologous TILs with additional immune activation via an exogenous transgene.
The scope also includes modified human TILs that contain an insertion, deletion, or mutation in an endogenous gene selected from a specified panel beyond SOCS1, including ANKRD11 and other listed genes. The content supports broader genetic engineering of TILs for cancer treatment while maintaining the autologous TIL administration framework.
Claims Coverage
The independent claim covers autologous, in vitro engineered TIL therapy with SOCS1 gene modulation. Dependent claims further specify immune-activating transgene content, cancer types, and additional endogenous gene targets.
Autologous modified human TILs with reduced SOCS1 expression
Administering a therapeutically effective amount of autologous modified human tumor infiltrating lymphocytes that have been modified in vitro to comprise an insertion, deletion, or mutation in an endogenous SOCS1 gene, wherein endogenous SOCS1 gene expression is reduced relative to unmodified human TILs obtained from the subject.
Exogenous transgene expressing an immune-activating molecule
Using modified human TILs that further comprise an exogenous transgene expressing an immune-activating molecule selected from cytokines, chemokines, co-stimulatory molecules, activating peptides, and antibodies or antigen-binding fragments.
Cancer treatment for specified cancer types
Limiting the cancer being treated to leukemia, lymphoma, or a solid tumor, and further narrowing to melanoma and lung cancer.
Engineered insertion, deletion, or mutation in an endogenous gene panel beyond SOCS1
Using modified human TILs that further contain an insertion, deletion, or mutation in an endogenous gene selected from a specified panel including ANKRD11 and other listed genes.
Overall, the claim coverage centers on autologous in vitro engineered TILs with reduced endogenous SOCS1 gene expression, optionally combined with an exogenous transgene expressing an immune-activating molecule, narrowed cancer types, and expanded endogenous engineering to a defined gene panel beyond SOCS1.
Stated Advantages
Enhances immune effector functions, including proliferation, tumor infiltration, persistence, viability, cytotoxicity, and resistance to exhaustion.
Documented Applications
Treating cancer in a subject in need thereof by administering a therapeutically effective amount of autologous modified human TILs engineered to reduce endogenous SOCS1 gene expression.
Treating cancer selected from leukemia, lymphoma, or a solid tumor.
Treating melanoma.
Treating lung cancer.
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