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-11459544-B2
Publication Date
2022-10-04
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 administering to a subject an effective amount of a modified human immune effector cell for treating cancer. The modified human immune effector cell comprises an inactivating nucleic acid mutation in an SH2 domain of an endogenous SOCS1 gene, and endogenous SOCS1 gene expression and/or function is reduced relative to an unmodified human immune effector cell. The inactivating nucleic acid mutation is an insertion, deletion, or mutation in the SH2 domain.
The disclosure further describes modified immune effector cells, including T cells such as CAR-T/TCR-T and TILs, with reduced expression and/or function of endogenous target genes, including immune checkpoint targets and other regulatory genes. Examples explicitly discussed include PDCD1, CTLA4, LAG3, TIGIT, NRP1, HAVCR2, IKZF1, IKZF2, IKZF3, FOXP3, SOCS1, CBLB, BCOR, and ANKRD11, as well as multi-gene combinations of endogenous genes for reduced expression and/or function.
The disclosure also defines gene-regulating systems for achieving reduced expression and/or function, including RNA interference and antisense, and CRISPR/Cas systems with guide RNAs and Cas endonucleases, including examples such as Cas9 and other Cas systems, as well as zinc finger and TALEN systems. The description includes optional combination with immune checkpoint inhibitory antibodies and frames the modified cells as useful for enhanced immunotherapy performance.
Claims Coverage
Two independent claim themes are presented across the input items: treating cancer using a modified human immune effector cell with an inactivating nucleic acid mutation in the SH2 domain of endogenous SOCS1, and reducing endogenous SOCS1 expression and/or function through that mutation. The dependent claims refine the modified cell, gRNA/Cas targeting, additional endogenous genes, CAR use, specified cancer categories, and optional checkpoint-inhibitory antibodies, yielding six recurring inventive features.
Inactivating socs1 sh2 domain to reduce socs1 expression and/or function
A method of treating cancer in a subject by administering an effective amount of a modified human immune effector cell comprising an inactivating nucleic acid mutation in an SH2 domain of an endogenous SOCS1 gene, wherein endogenous SOCS1 gene expression and/or function is reduced relative to an unmodified human immune effector cell, and wherein the inactivating nucleic acid mutation is an insertion, deletion, or mutation in the SH2 domain.
Expanding reduced-expression targets to additional endogenous genes
The modified human immune effector cell comprises an inactivating nucleic acid mutation in an endogenous gene selected from a specified group of endogenous genes.
gRNA/Cas endonuclease targeting of the socs1 sh2 domain
The modified human immune effector cell further includes one or more gRNA and a Cas endonuclease, where the gRNA targeting domain sequence binds to a target nucleic acid sequence in the SH2 domain of the endogenous SOCS1 gene.
Using an engineered car immune receptor
The method is performed using an engineered immune receptor that is a chimeric antigen receptor (CAR).
Treating specified cancer categories
The method is applied to cancer selected from a leukemia, a lymphoma, and a solid tumor.
Optional administration of checkpoint-inhibitory antibodies
The method further comprises administering to a subject an antibody or binding fragment that specifically binds to and inhibits the function of the proteins encoded by NRP1, HAVCR2, LAG3, TIGIT, CTLA4, or PDCD1.
Overall, the claims coverage centers on administering modified human immune effector cells with an insertion, deletion, or mutation in the SOCS1 SH2 domain that reduces SOCS1 expression and/or function, with further refinements adding additional endogenous targets, gRNA/Cas-based SH2 targeting, CAR use, specified cancer categories, and optional checkpoint-inhibitory antibodies.
Stated Advantages
In vivo validation indicates improved anti-tumor efficacy and effector function with dual gene editing in adoptively transferred T cells, including increased tumor growth inhibition and strong or near-complete inhibition of lung metastases for Socs1/Cblb dual editing.
SOCS1 SH2-domain targeting guides are described as increasing T cell survival/proliferation.
Enhanced immunotherapy performance is described through increased proliferation, tumor infiltration, persistence, resistance to exhaustion, and cytotoxicity.
Documented Applications
In vivo use with adoptively transferred T cells, including an OT1/B16-Ova model and a B16-F10 metastatic model (lung metastases inhibition), with additional evaluations in MC38gp100 and B16-F10 lung metastases for other dual editing combinations.
Assessment across engineered receptors and TILs, including experiments involving PD-1 and LAG3 where combination editing did not enhance tumor growth inhibition compared to single edits.
An early-phase (Phase I) clinical study outline for relapsed/refractory metastatic melanoma after anti–PD-1 therapy.
Treating cancer in a subject in need thereof using a modified human immune effector cell with an inactivating nucleic acid mutation in the SOCS1 SH2 domain.
Treatment is described for cancer including solid tumors and PD1-resistant or PD1-insensitive cancers.
The method is applied to cancer selected from leukemia, lymphoma, and solid tumor.
Optional combination therapy is described with an antibody or binding fragment that inhibits function of proteins encoded by NRP1, HAVCR2, LAG3, TIGIT, CTLA4, or PDCD1.
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