Chimeric antigen receptor t cells and methods of use thereof
AssigneeAugusta University Research Institute, Inc.
InventorGang ZHOU
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Abstract
Disclosed herein are engineered polyfunctional CD4+ T cells/CAR T cells and methods of their use for the treatment of cancers. One embodiment provides a method of producing polyfunctional CD4+ T cells by constitutively activating STAT5A in the cells to induce a polyfunctional phenotype. Also provided is a method of reversing exhaustion in tumor-specific CD4+ T cells by engineering the cells to express Fos, Jun, Nr4a1, or combinations thereof but not express Tox, Pdcd1, Ctla4, Haver2, Lag3, Tigit, Slam6, Nrf4a2, and administering the engineered cells to a subject.
Claims26
A method of adoptive cell transfer comprising:
- administering a population of modified CD4+ T cells genetically engineered to express one or more of genes selected from the group consisting of Fos, Jun, Nr4a1, and combinations thereof and not express one or more genes selected from the group consisting of Tox, Pdcd1, Ctla4, Haver2, Lag3, Tigit, Slam6, Nrf4a2, and combinations thereof to a subject in need thereof in an amount effective to induce an immune response.
A method of adoptive transfer comprising:
- isolating CD4+ T cells from a subject,
- genetically engineering the CD4+ T cell to constitutively express Stat5a activity, wherein the constitutive STAT5a activity induces expression of one or more of Fos, Jun, Nr4a1, or combinations thereof and silences expression of one or more of Tox, Pdcd1, Ctla4, Haver2, Lag3, Tigit, Slam6, Nrf4a2, or combinations thereof, and
- administering the genetically engineered CD4+ T cells to the subject in an amount effective to induce an immune response.
A method of producing polyfunctional T cells comprising:
- inducing the expression of Fos, Jun, Nr4a1, or combinations thereof in a population of T cells in an amount effective to induce polyfunctionality, and
- silencing the expression of Tox, Pdcd1, Ctla4, Haver2, Lag3, Tigit, Slam6, Nrf4a2, or a combination thereof in the population of T cells, wherein the gene expression phenotype induces polyfunctionality in the population of T cells.
A method of reversing T cell exhaustion in a population of tumor-specific CD4+ T cells in a patient in need thereof, comprising:
- increasing the expression of one or more genes selected from the group consisting of Fos, Jun, Nr4a1, and combinations thereof in a population of T cells in an amount effective to induce polyfunctionality,
- decreasing the expression one or more genes selected from the group consisting of Tox, Pdcd1, Ctla4, Haver2, Lag3, Tigit, Slam6, Nrf4a2, and combinations thereof in the population of T cells in an amount effective to induce polyfunctionality, wherein the gene expression phenotype reverses exhaustion and induces polyfunctionality in the population of CD4+ T cells, and
- administering the population of CD4+ T cells to the subject in need thereof, wherein the administered CD4+ T cells induce an immune response in the tumor.
Dependencies are inferred from the claim text.