Intracellular genomic transplant and methods of therapy
Inventors
Moriarity, Branden • Webber, Beau • Choudhry, Modassir • 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-11266692-B2
Publication Date
2022-03-08
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
Despite remarkable advances in cancer therapeutics, many tumor types remain resistant to chemotherapy, radiotherapy, or biotherapy, especially in advanced stages that are not addressable through surgery. Recent advances in genetic engineering of lymphocytes have led to cases of tumor remission, mainly in hematologic tumors, but broader application to solid tumors is limited by the lack of identifiable molecules that are tumor-specific and accessible for targeted destruction.
The disclosed invention addresses this problem by providing genetically modified compositions, such as non-viral vectors and T cells, that carry transgenes encoding cancer-specific T Cell Receptors (TCRs) recognizing unique immunogenic mutations found in a patient's cancer. These transgenes are inserted into T cells using non-viral methods like CRISPR, TALEN, or transposon-based techniques, which enable the expansion of immunotherapy to many types of cancer beyond hematologic tumors.
Engineered cells comprise at least one gene disruption, often in immune checkpoint genes such as PD-1, into which a non-virally integrated TCR sequence is inserted. The engineered TCR sequence may comprise two chains (alpha and beta) producing a functional receptor that recognizes antigen in the context of major histocompatibility complex (MHC) class I or II molecules, including cancer-specific mutations identified by whole-exomic sequencing. These engineered cells can be primary immune cells, capable of expansion ex vivo or in vivo, autologous or non-autologous, and compatible with good manufacturing practices (GMP) for therapeutic use in cancer, infections, autoimmune disorders, or graft-versus-host disease.
Claims Coverage
The patent includes multiple independent claims covering pharmaceutical compositions of engineered human primary lymphocytes and genetically modified human cells containing genomic disruptions in cytokine-inducible SH2-containing protein genes, and engineered cells expressing exogenous T cell receptors or chimeric antigen receptors.
Genomic disruption in cytokine-inducible SH2-containing protein gene in human primary lymphocytes
A population of engineered human primary lymphocytes comprising a genomic disruption within a cytokine-inducible SH2-containing protein gene target sequence (SEQ ID NO: 75-86) wherein the disruption comprises an endonuclease-mediated indel, resulting in reduced expression of the encoded protein compared to cells lacking the disruption.
Tumor infiltrating lymphocytes genetically modified with exogenous receptors
Engineered human primary lymphocytes, including tumor infiltrating lymphocytes, comprising genomic disruptions in cytokine-inducible SH2-containing protein genes and further comprising at least one exogenous T cell receptor or chimeric antigen receptor targeting antigens such as BCMA, HER-2, CD19, or MUC1.
Genetically modified human cells with disrupted cytokine-inducible SH2-containing protein gene
A genetically modified human cell comprising a genomic disruption within SEQ ID NO: 75-86 suppressing or eliminating expression of the encoded cytokine inducible SH2-containing protein gene through an endonuclease-mediated indel, particularly within exon 2 or 3, and the cell being tumor infiltrating lymphocytes, peripheral blood lymphocytes, T cells, NK cells, or further comprising exogenous TCR or chimeric antigen receptors targeting BCMA, HER-2, CD19, or MUC1.
The claims principally cover engineered human lymphocytes, including tumor infiltrating lymphocytes, comprising genomic disruptions in cytokine-inducible SH2-containing protein genes achieved via endonuclease-mediated indels and expressing exogenous antigen receptors such as TCRs or CARs, allowing targeting of cancer-associated antigens.
Stated Advantages
The disclosed compositions and methods enable high efficiency gene transfer and expression with increased cell survival rates.
They provide efficient introduction of recombinogenic double strand breaks and favor homologous directed repair over non-homologous end joining, enhancing the recovery and expansion of homologous recombinants.
The approaches reduce cellular toxicity associated with exogenous DNA introduction, improving viability and therapeutic compatibility of engineered cells.
The inventions facilitate extending immunotherapy beyond hematologic tumors to various cancer types including solid tumors.
Documented Applications
Use of genetically modified compositions and engineered cells for treating cancer by introducing cancer-specific T cell receptors that recognize unique immunogenic mutations in patient's cancer.
Adoptive cell transfer-based immunotherapy to treat metastatic cancer patients using autologous or non-autologous engineered T cells.
Treatment of infections, autoimmune disorders, or graft-versus-host disease using cells engineered with non-viral integration of exogenous receptors and gene disruptions.
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