Chimeric antigen receptor T cells and methods of use thereof
View Patent ↗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.
1 . A method of adoptive transfer comprising:
a) isolating CD4 + and CD8 + T cells from a subject,
b) expanding the CD4 + and CD8 + T cells ex vivo,
c) genetically engineering the CD4 + and CD8 + T cells to produce polyfunctional CD4 + and CD8 + T cells which express a cluster of differentiation 19 protein chimeric antigen receptor (CD 19CAR) and constitutively express signal transducer and activator of transcription 5 (Stat5a) by transducing the CD4 + and CD8 + T cells with SEQ ID NO: 1 or 2, and
d) administering the polyfunctional CD4 + and CD8 + T cells expressing CD19CAR and constitutively expressing Stat5a to the subject in an amount effective to induce an immune response to cancer,
wherein the subject has a hematological cancer,
wherein the polyfunctional CD4 + and CD8 + T cells expressing CD19CAR reverse exhaustion in tumor-specific CD4 + and CD8 + T cells and the constitutive STAT5a activity induces epigenetic changes and changes in expression in comparison to control CD4 + and CD8 + T cells in hematological cancer, and
wherein the polyfunctional CD4 + and CD8 + T cells expressing CD19CAR and constitutively expressing Stat5a, when administered in combination, synergistically enhances tumor infiltration and retention of CD4 + and CD8 + T cells compared to control CD4 + and CD8 + T cells in hematological cancer.
2 . The method of claim 1 , wherein the immune response is production and release of cytokines from the polyfunctional CD4 + and CD8 + T cells, wherein the cytokines are selected from the group consisting of IFNγ, IL4, IL13, and GMCSF.
3 . The method of claim 1 , wherein the polyfunctional CD4 + and CD8 + T cells are administered to the subject in an aqueous solution by parenteral administration or infusion.
4 . The method of claim 1 , wherein the polyfunctional CD4 + and CD8 + T cells are autologous.
5 . The method of claim 1 , wherein the immune response reduces or prevents tumor growth or progression, or a combination thereof, compared to untreated tumors, in the subject in need thereof.
6 . The method of claim 1 , wherein the hematologic cancer is B cell lymphoma.