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-11642374-B2
Publication Date
2023-05-09
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 relates to genetically modified compositions, specifically non-viral vectors and T cells, for treating cancer, as well as methods of making and using these genetically modified compositions in cancer treatment. The compositions enable identification of cancer-specific T cell receptors (TCRs) that recognize unique immunogenic mutations in a patient’s cancer and facilitate targeted immunotherapy for any cancer type by integrating these cancer-specific TCR transgenes into T cells through non-viral methods such as CRISPR, TALEN, transposon-based, ZEN, meganuclease, or Mega-TAL.
The invention overcomes limitations in extending immunotherapy beyond hematologic tumors to solid tumors, which are hindered by the absence of identifiable molecules uniquely expressed by solid tumor cells. It achieves this by enabling non-viral insertion of transgenes encoding cancer-specific TCRs that recognize mutations identified by whole-exomic sequencing, thereby promoting efficient integration into immune cells with gene disruptions, particularly in immune checkpoint genes such as PD-1.
The engineered cells can be primary immune cells including T cells, stem cells, and progenitor cells, which can be autologous or allogeneic. The methods involve introducing non-viral nucleic acids with recombination arms complementary to genomic regions to catalyze homologous recombination-mediated integration that disrupts specific genes, augmented by homologous recombination enhancers, and reducing cellular toxicity with modifier compounds targeting DNA sensing pathways. This approach produces engineered cellular therapies suitable for expansion and administration in vivo or ex vivo.
Claims Coverage
The patent includes multiple independent claims focusing on engineered human primary immune cells for cancer therapy, featuring at least one gene disruption and integration of exogenous receptor sequences specific for cancer neo-antigens.
Pharmaceutical composition comprising engineered immune cells with CISH gene disruption
A pharmaceutical composition comprising an ex vivo engineered human primary immune cell having a genomic disruption within a cytokine inducible SH2-containing protein (CISH) gene target sequence with an endonuclease-mediated indel and at least one nucleic acid encoding an exogenous functional T cell receptor or chimeric antigen receptor that binds a cancer neo-antigen arising from a somatic mutation.
Integration of receptor sequences into disrupted CISH or TCR loci
The exogenous functional TCR or chimeric antigen receptor is expressed by the engineered cell and integrated into the genomic disruption in CISH gene or T Cell Receptor Alpha Constant or Beta Locus sequences.
Use of CRISPR system for gene disruption
Genomic disruption of the CISH gene is performed by a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) system.
Engineered cells targeting a broad range of cancers with neo-antigen specificity
The engineered immune cells are for treating various cancers, including epithelial, bladder, bone, brain, breast, gastrointestinal, leukemia, lymphoma, melanoma, ovarian, prostate, sarcoma, stomach, thyroid, and others, where the exogenous receptor binds somatic mutation-derived neo-antigens expressed by cancer cells.
Integration method using viral vectors including AAV
The exogenous nucleic acid encoding the receptor can be introduced via viral vectors such as adeno-associated virus (AAV) vectors.
Overall, the claims cover engineered human primary immune cells with targeted genomic disruptions, particularly in the CISH gene, combined with integration and expression of cancer neo-antigen binding exogenous TCR or CAR sequences. The claims encompass compositions, methods of disruption using CRISPR, and viral vector-mediated insertion applicable to various cancers.
Stated Advantages
High efficiency gene transfer and controlled expression of engineered TCRs in immune cells.
Increased cell survival rates and reduced cellular toxicity during genetic modification.
Enhanced recovery and expansion of homologous recombinants favoring homology-directed repair over non-homologous end joining.
Broad applicability to a wide range of cancer types including solid tumors, extending immunotherapy beyond hematologic malignancies.
Documented Applications
Treatment of various cancers including epithelial, bladder, bone, brain, breast, esophageal, gastrointestinal, hematopoietic malignancies, leukemia, liver, lung, lymphoma, myeloma, ovarian, prostate, sarcoma, stomach, thyroid, and other listed cancers by adoptive cell transfer using genetically engineered immune cells.
Use in autologous or allogeneic cell transplantation for cancer immunotherapy.
Combination therapies involving transplantation, immunotherapy, chemotherapy, radiation, and immunosuppressive agents in patients receiving engineered immune cells.
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