Gene-regulating compositions and methods for improved immunotherapy
Inventors
Benson, Micah • Merkin, Jason • Kryukov, Gregory V. • Shenker, Solomon Martin • Schlabach, Michael • Tubo, Noah
Assignees
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Publication Number
US-11111493-B2
Publication Date
2021-09-07
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 relates to gene-regulating compositions and engineered immune effector cells for improving immunotherapy. It provides a primary human T cell that comprises a modified endogenous ZC3H12A gene and an engineered antigen receptor that specifically binds to a tumor antigen. In the modified T cell, ZC3H12A protein expression and/or function is reduced relative to a primary human T cell expressing the endogenous ZC3H12A gene.
The gene-regulating strategy reduces expression and/or function of endogenous target genes to improve proliferation, tumor infiltration, persistence, resistance to exhaustion, and cytotoxicity. The document further focuses on inhibiting/modulating ZC3H12A (Regnase-1, MCPIP1) and other endogenous targets such as MAP4K1 (HPK1), NR4A3, and checkpoint-related genes exemplified by PDCD1 (PD-1), CTLA4, LAG3, TIGIT, HAVCR2 (TIM-3), and NRP1.
The gene-regulating system is implemented using multiple modalities, including CRISPR/Cas with guide RNA and Cas/Cas orthologs, zinc-finger nucleases, TALENs, and RNA interference molecules such as siRNA, shRNA, microRNA, antagomiR, and antisense RNA. The document also encompasses delivery and production concepts for modified cells and pharmaceutical compositions, including autologous and/or allogeneic cells, vectors encoding gRNA/Cas or RNP complexes, and therapeutic regimens for cell proliferative disorders.
Claims Coverage
The identified claims center on a primary human T cell with reduced endogenous ZC3H12A protein expression and/or function together with an engineered antigen receptor that specifically binds to a tumor antigen. Dependent claim refinements further define the gene-regulating system, target sequence constraints, alternative modalities, and immune-cell subsets.
Modified endogenous ZC3H12A gene with reduced expression and/or function
A primary human T cell comprising a modified endogenous ZC3H12A gene wherein ZC3H12A protein expression and/or function is reduced relative to a primary human T cell expressing the endogenous ZC3H12A gene.
Engineered antigen receptor specific for a tumor antigen
The primary human T cell comprises an engineered antigen receptor that specifically binds to a tumor antigen.
Cas endonuclease specified as Cas9
The gene-regulating system specifies a Cas endonuclease as a Cas9 protein.
Enumerated target sequence constrained to SEQ ID NOs 1065-1264
The gene-regulating system includes a target sequence selected from SEQ ID NOs: 1065-1264.
Alternative gene-regulating system using zinc finger nuclease or TALEN
The gene-regulating system includes either a zinc finger nuclease with a zinc finger binding domain or a TALEN with a TAL effector domain.
RNA interference molecule selection for gene regulation
The gene-regulating system includes an RNA interference molecule selected from siRNA, shRNA, microRNA (miR), antagomiR, or antisense RNA.
Restriction to specific primary human T cell subsets
The primary human T cell is selected from CD4+ T cells, CD8+ T cells, Th1 cells, Th2 cells, or Th17 cells.
The claims collectively cover a primary human T cell engineered to bind a tumor antigen while carrying a modified endogenous ZC3H12A gene that reduces ZC3H12A protein expression and/or function. The dependent features further specify Cas9, enumerated target sequences, alternative gene-regulation modalities, RNA interference embodiments, and defined T cell subsets.
Stated Advantages
Improves effector phenotypes by reducing expression and/or function of endogenous target genes, including improved proliferation, tumor infiltration, persistence, resistance to exhaustion, and cytotoxicity.
Documented Applications
Therapeutic regimens for cell proliferative disorders, including cancers such as melanoma and colorectal.
Immunotherapy contexts including PD-1/PD-L1-insensitive contexts.
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