Method for generating immune cells resistant to arginine and/or tryptophan depleted microenvironment
Inventors
Poirot, Laurent • SIMON, Mathieu
Assignees
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Publication Number
US-12171820-B2
Publication Date
2024-12-24
Expiration Date
Abstract
The present invention pertains to engineered immune cells, method for their preparation and their use as medicament, particularly for immunotherapy. The engineered immune cells of the present invention are characterized in that at least one gene selected from a gene encoding GCN2 and a gene encoding PRDM1 is inactivated or repressed. Such modified Immune cells are resistant to an arginine and/or tryptophan depleted microenvironment caused by, e.g., tumor cells, which makes the immune cells of the invention particularly suitable for immunotherapy. The invention opens the way to standard and affordable adoptive immunotherapy strategies using immune cells for treating different types of malignancies.
Core Innovation
The invention relates to an isolated population of engineered immune cells comprising inactivation of PR domain zinc finger protein 1 (PRDM1) and general control nonderepressible 2 (GCN2) genes. The inactivation is performed by cleavage with a rare-cutting endonuclease, and the engineered cells are directed to overcoming an arginine/tryptophan-depleted tumor microenvironment, including conditions mediated by arginase I and IDO1/IDO1-related pathways.
The core approach uses engineered immune cells, including T cells, that become resistant to tumor microenvironments characterized by arginine depletion and tryptophan depletion. The specification further describes genome engineering using rare-cutting endonucleases including TALE nucleases, meganucleases, ZFNs, and RNA-guided endonucleases such as Cas9.
Optional additional genetic features are described, including non-alloreactivity via disruption of TCR components, such as TCRα, and optional CAR expression against selected tumor antigens including CD19, CD33, CD123, CS1, BCMA, and EGFRvIII. Therapeutic use is directed to treating cancers, including solid and liquid cancers and specified malignancies, using the engineered immune cells.
Claims Coverage
The independent claim covers an isolated population of engineered immune cells with two core inventive features: PRDM1 and GCN2 inactivation, where the inactivation is by cleavage with a rare-cutting endonuclease. Dependent claims refine the invention by specifying particular rare-cutting endonuclease categories, defining PRDM1 and GCN2 as particular human variants or sequence-identity functional variants, and optionally adding non-alloreactivity and CAR-related targeting features.
Dual gene inactivation of PRDM1 and GCN2 by rare-cutting endonuclease cleavage
An isolated population of engineered immune cells comprising inactivation of PR domain zinc finger protein 1 (PRDM1) and general control nonderepressible 2 (GCN2) genes, wherein the inactivation is by cleavage with a rare-cutting endonuclease.
Human GCN2 sequence identity constraint
The engineered immune cell population includes GCN2 that is human GCN2 or a functional variant having at least about 80% sequence identity across the full length.
Human PRDM1 sequence identity constraint
The claim specifies that the engineered immune cell population includes PRDM1 that is human PRDM1 or a functional variant with at least about 80% sequence identity across its entire length.
Rare-cutting endonuclease type selection
The engineered immune cell population is defined such that the rare-cutting endonuclease used is a TALE-nuclease, meganuclease, zinc-finger nuclease (ZFN), or an RNA- or DNA-guided endonuclease.
Cas9 as the RNA-guided endonuclease
The population of engineered immune cells where the RNA-guided endonuclease is Cas9.
CAR targeting at least one malignant-cell surface antigen
The engineered immune cells express a Chimeric Antigen Receptor (CAR) targeting at least one antigen displayed on the surface of a malignant cell.
Overall, the claim set centers on an engineered immune cell population with PRDM1 and GCN2 inactivated by rare-cutting endonuclease cleavage, refined by specifying human PRDM1/GCN2 variant identity constraints and by narrowing the endonuclease categories, including Cas9. Additional refinements include optional CAR-based targeting of malignant-cell surface antigens.
Stated Advantages
Engineered immune cells are made resistant to arginine/tryptophan-depleted tumor microenvironments.
Improved survival under arginine depletion and arginase activity is described in examples.
Documented Applications
Treating cancers, including solid and liquid cancers, using the engineered immune cells.
Adoptive/off-the-shelf allogeneic immunotherapy potential is described for the engineered immune cells.
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