T-cells modified to overexpress PHF19
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-11883431-B2
Publication Date
2024-01-30
Expiration Date
2038-06-05
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Abstract
Provided is a mammalian T cell modified to express the Phf19 at a level that is higher than the level of Phf19 expressed by a T cell that has not been modified to express Phf19. Provided is a genetically-modified mammalian T cell comprising a genetic expression vector comprising (a) virally-, bacterially-, or both virally- and bacterially-derived genetic sequences and (b) a genetic sequence encoding Phf19, whereby the genetic sequence encoding Phf19 within the vector is expressed within the T cell. Pharmaceutical compositions, methods of treating a disease, and methods of inhibiting the differentiation of T cells by epigenetic reprogramming are also provided.
Core Innovation
The invention provides a genetically-modified mammalian T cell that expresses Phf19 at levels higher than unmodified T cells. This modification can be achieved using a genetic expression vector comprising virally-, bacterially-, or both virally- and bacterially-derived genetic sequences encoding Phf19, allowing elevated Phf19 expression within the T cell. The T cells can be isolated or purified populations, including CD8+ T cells, and may also comprise an antigen-specific receptor such as a T cell receptor (TCR) or a chimeric antigen receptor (CAR).
The invention addresses obstacles faced in adoptive cell transfer therapy, particularly the declining in vivo proliferation, survival, persistence, and effector functions of transferred T cells, which may rapidly become functionally exhausted. T cell exhaustion is characterized by poor effector function, sustained expression of inhibitory receptors, and a distinct transcriptional state, limiting immunotherapy's efficacy for cancer and chronic viral diseases. Existing methods have not adequately improved the production and therapeutic functionality of such T cells.
The invention thus provides methods and compositions to enhance adoptive cell therapy by overexpressing Phf19 in T cells, which epigenetically reprograms T cell fate. This overexpression inhibits T cell terminal differentiation and exhaustion, thereby increasing in vivo proliferation, persistence, anti-tumor and anti-viral activities, and promoting formation of memory precursor cells. The chromatin-binding capacity of Phf19, via key amino acids in its Tudor domain, recruits the PRC2 complex for targeting histone modifications, underlying its role in regulating CD8+ T cell differentiation and functional exhaustion.
Claims Coverage
The patent contains multiple independent claims focusing on genetically modified mammalian T cells that overexpress Phf19 and methods of using these cells for therapy.
T cell comprising a genetic expression vector encoding Phf19
A mammalian T cell with an antigen-specific receptor (TCR or CAR) that includes a genetic expression vector encoding Phf19, enabling overexpression of Phf19 within the T cell.
T cell comprising a vector with virally- or bacterially-derived sequences encoding Phf19
A T cell comprising a genetic expression vector comprising virally-, bacterially-, or both virally- and bacterially-derived genetic sequences with a genetic sequence encoding Phf19, which is expressed within the T cell.
Use of CD8+ human T cells
The T cell is specified to be CD8+ and/or human, adapted for enhanced therapeutic application against diseases.
Pharmaceutical composition comprising modified T cells
A pharmaceutical composition containing genetically-modified T cells overexpressing Phf19 along with a pharmaceutically acceptable carrier.
Method of treating cancer or chronic viral diseases using modified T cells
A method of treating cancer or chronic viral disease in a mammal by administering an effective amount of T cells modified to overexpress Phf19 and with antigen-specific receptors targeting disease-associated antigens.
The independent claims collectively cover methods and compositions involving mammalian T cells engineered to overexpress Phf19 via genetic vectors, specifying parameters such as antigen-specific receptors, cell type, vector composition, pharmaceutical compositions, and therapeutic uses in treating cancer and chronic viral diseases.
Stated Advantages
Increased in vivo proliferation, survival, and persistence of T cells compared to non-modified cells.
Enhanced anti-tumor and anti-viral activity of T cells.
Reduced terminal differentiation and senescence in CD8+ T cells.
Sustained polyfunctionality and cytokine production of modified T cells.
Improved long-term memory formation and superior therapeutic efficacy in adoptive cell transfer therapy.
Documented Applications
Treatment of cancer, including melanoma, leukemia, and HPV carcinoma.
Treatment of chronic viral diseases caused by viruses such as herpes viruses, influenza virus, hepatitis viruses, HIV, and others.
Enhancement of adoptive cell transfer therapies using genetically-modified T cells overexpressing Phf19.
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