T cells modified to overexpress c-Myb
Inventors
Gautam, Sanjivan • Ji, Yun • Gattinoni, Luca
Assignees
US Department of Health and Human Services
Publication Number
US-11098283-B2
Publication Date
2021-08-24
Expiration Date
2036-08-24
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Abstract
Provided is an isolated or purified T cell comprising an antigen-specific receptor, wherein the antigen-specific receptor is a T cell receptor (TCR) or a chimeric antigen receptor (CAR), wherein the T cell has been modified to express a transcription factor at a level that is higher than the level of the transcription factor expressed by a T cell that has not been modified to express the transcription factor, wherein the transcription factor is V-Myb Avian Myeloblastosis Viral Oncogene Homolog (c-Myb), a functional variant of c-Myb, or a functional fragment of c-Myb. Related populations of cells, pharmaceutical compositions, methods of treating a disease, and methods of inhibiting the differentiation of T cells are also provided.
Core Innovation
The invention provides an isolated or purified T cell comprising an antigen-specific receptor, which can be a T cell receptor (TCR) or a chimeric antigen receptor (CAR). The T cell is modified to express the transcription factor c-Myb, a functional variant, or fragment thereof, at a level higher than that expressed by an unmodified T cell. The modification inhibits differentiation of the T cell and results in a less differentiated phenotype, such as naïve (TN), T memory stem cell (TSCM), or central memory T cell (TCM), rather than effector memory T cell (TEM) phenotype.
The problem being addressed is that adoptive cell therapy suffers from obstacles including decreased in vivo persistence, survival, and anti-tumor activity of T cells after adoptive transfer, as well as challenges posed by increased differentiation of T cells. Current methods for producing cells for adoptive cell therapy and treatments for cancer and viral diseases have limitations in efficacy, necessitating improved methods.
The invention also provides methods of inhibiting differentiation of T cells via introduction of nucleic acids encoding c-Myb to increase expression, thereby producing T cells with a less differentiated phenotype. Pharmaceutical compositions comprising the modified T cells and methods of treating diseases, including cancer and viral diseases, with the modified T cells are also provided. The modified T cells exhibit enhanced proliferation, survival, persistence, and anti-tumor or anti-viral activity compared to unmodified T cells.
Claims Coverage
The patent includes multiple independent claims focused on modified T cells, methods of inhibiting T cell differentiation, and methods of treating diseases. There are three main groups of independent claims: compositions of T cells, methods of inhibiting differentiation, and methods of treatment.
T cells modified to overexpress c-Myb with inhibited differentiation
An isolated or purified T cell comprising an antigen-specific receptor (TCR or CAR) modified to express c-Myb at a level higher than unmodified T cells, wherein increased c-Myb expression inhibits T cell differentiation, and the T cell is CD8+, CD62L+, and KLRG1−.
Vector-mediated overexpression of c-Myb in T cells
A T cell comprising a vector with (i) nucleic acid encoding c-Myb and (ii) a heterologous nucleic acid, wherein the T cell expresses c-Myb at an increased level compared to T cells lacking the vector.
Method of inhibiting T cell differentiation by increasing c-Myb expression
A method introducing nucleic acid encoding c-Myb into isolated or purified T cells under conditions to increase c-Myb expression compared to cells lacking such nucleic acid, where increased expression inhibits T cell differentiation and the T cells are CD8+, CD62L+, and KLRG1−.
Method of treating or preventing disease by administering modified T cells
A method of treating or preventing cancer or viral disease in a mammal by administering a population of T cells comprising a cancer or viral antigen-specific receptor (TCR or CAR) and modified to overexpress c-Myb.
The claims cover T cells modified to overexpress c-Myb that inhibits differentiation, nucleic acid vectors mediating c-Myb overexpression, methods of inhibiting T cell differentiation via c-Myb upregulation, and methods of treating cancer or viral diseases by administering such modified T cells.
Stated Advantages
Modified T cells have increased in vivo proliferation compared to unmodified T cells.
Enhanced survival and persistence of T cells that overexpress c-Myb.
Improved anti-tumor and anti-viral activity of T cells modified to overexpress c-Myb.
The T cells modified to overexpress c-Myb have a less differentiated phenotype, which is believed to facilitate greater expansion and suitability for adoptive cell therapy.
Documented Applications
Producing T cells modified to overexpress c-Myb for use in adoptive cell therapy.
Treating or preventing cancer by administering T cells overexpressing c-Myb with antigen-specific TCR or CAR.
Treating or preventing viral diseases by administering T cells overexpressing c-Myb with antigen-specific TCR or CAR.
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