Modified cells and methods of therapy
Inventors
Moriarity, Branden • Webber, Beau • Choudhry, Modassir • McIvor, R. Scott • Largaespada, David • Rosenberg, Steven A. • Palmer, Douglas C. • Restifo, Nicholas P.
Assignees
Intima Bioscience Inc • University of Minnesota System • US Department of Health and Human Services
Publication Number
US-11583556-B2
Publication Date
2023-02-21
Expiration Date
2036-07-29
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Abstract
Genetically modified compositions, such as non-viral vectors and T cells, for treating cancer are disclosed. Also disclosed are the methods of making and using the genetically modified compositions in treating cancer.
Core Innovation
The invention discloses genetically modified compositions, including non-viral vectors and T cells, for treating cancer. It provides methods of making and using these genetically modified compositions in cancer treatment. Engineered cells are described comprising at least one gene disruption and at least one non-virally integrated T cell receptor (TCR) sequence, where the gene can be disrupted by the non-virally integrated TCR sequence. The immune checkpoint genes targeted include, for example, PD-1 and others such as ADORA, CD276, CTLA4, and CISH.
The engineered TCR sequences can produce functional TCR recognizing antigens in the context of major histocompatibility complex (MHC) class I (e.g., HLA-A02) or class II, including mutated cancer neoantigens identified by whole-exomic sequencing. The engineered cells can be primary immune cells including T cells, stem cells, or progenitor cells, which can be autologous or non-autologous to a subject. The methods include non-viral insertion of the TCR sequence into a genomic double strand break region created by nucleases such as CRISPR, TALEN, meganuclease, or Mega-TAL, optionally aided by homologous recombination enhancers and modifiers that reduce cellular toxicity.
A major problem addressed is the limited efficacy of genetic engineering of lymphocytes for immunotherapy of solid tumors due to lack of tumor-specific target molecules and issues with current viral vector methods. The invention solves this by enabling identification of cancer-specific TCRs that recognize unique immunogenic mutations, and their precise insertion into immune cells via non-viral methods that disrupt immune checkpoint genes (e.g., PD-1) to improve T cell function against various cancer types, extending immunotherapy beyond hematologic malignancies.
Claims Coverage
The claims cover methods and compositions involving genetically modified human natural killer (NK) cells with specific gene disruptions and optionally expressing exogenous receptors for treating cancer.
Method of treating cancer using genetically modified NK cells with CISH gene disruption
Administering to a human subject an effective amount of genetically modified human natural killer cells that have a genomic disruption in the cytokine inducible SH2-containing (CISH) gene suppressing or eliminating CISH protein expression, in a pharmaceutical composition with carriers or excipients.
Optionally combining immunodepleting agents to improve therapy
Further comprising administration of cyclophosphamide, fludaribine, or both to transiently deplete host lymphocytes in the subject before or during treatment.
Autologous NK cells for therapy
The genetically modified NK cells used in treatment can be autologous to the treated human subject.
Nature of genomic disruption in CISH gene
The genomic disruption in the CISH gene can be a nucleotide insertion or deletion resulting in gene suppression or elimination.
Incorporation of exogenous antigen receptors
The genetically modified human NK cells can further comprise an exogenous T cell receptor (TCR) or chimeric antigen receptor (CAR).
Target specificity of exogenous receptors
The exogenous TCR or CAR expressed by the modified NK cells can bind a cancer neo-antigen.
Source of genetically modified cells
The genetically modified human NK cells can be derived from induced pluripotent stem cells.
Further genomic modifications for enhanced function
The genetically modified human NK cells can additionally comprise genomic disruption of transforming growth factor beta receptor II (TGFBRII) gene to potentially augment therapeutic effect.
The claims primarily protect a method of treating cancer using genetically modified human NK cells with disrupted CISH expression, optionally expressing antigen receptors and combined with immunosuppressive regimens, highlighting various genetic modifications and embodiments.
Stated Advantages
Provides high efficiency gene transfer and expression, increasing cell survival rates and favoring homology directed repair (HDR) over non-homologous end joining (NHEJ).
Enables safe and efficient non-viral integration of cancer-specific TCR genes into immune cells, allowing expanded immunotherapy to solid tumors beyond hematologic malignancies.
Reduction of cellular toxicity induced by exogenous DNA via compounds and genetic modifications, improving cell viability during genomic engineering.
Use of homologous recombination enhancers facilitates gene insertion at desired genomic sites with increased efficiency and precision.
Allows generation of autologous or allogeneic engineered T cells compatible with good manufacturing practices (GMP) for potential clinical application.
Documented Applications
Treatment of various cancers including solid tumors by adoptive cell transfer of engineered T cells or NK cells with tumor-specific TCRs or CARs.
Immunotherapy leveraging genetically modified immune cells to recognize neoantigens identified by whole-exomic sequencing in cancer patients.
Treatment of infections, autoimmune disorders, or graft-versus-host disease (GVHD) by engineered cells disrupting immune checkpoint genes.
Use of genetically modified NK cells with CISH gene disruption for cancer therapy potentially combined with immunodepleting agents.
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