Chimeric antigen receptor T cells and methods of use thereof
Inventors
Assignees
Augusta University • Augusta University Research Institute Inc
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Publication Number
US-12668777-B2
Publication Date
2026-06-30
Expiration Date
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.
Core Innovation
The invention relates to engineered polyfunctional CD4+ T cells and CD19 CAR T cells for cancer immunotherapy in a subject with a hematological cancer. The engineered T cells are generated as polyfunctional CD4+ and CD8+ T cells and are characterized by constitutively expressing signal transducer and activator of transcription 5 (Stat5a). The engineered cells are designed to induce an immune response to cancer upon adoptive transfer.
The invention provides a constitutively active STAT5a activity that induces epigenetic changes and changes in expression compared to control CD4+ and CD8+ T cells in hematological cancer. The engineered polyfunctional CD4+ and CD8+ T cells reverse exhaustion in tumor-specific CD4+ and CD8+ T cells. The constitutive STAT5a activity is associated with reduced exhaustion markers and an exhaustion-resistant functional phenotype.
The invention further includes CD4+ and CD8+ polyfunctional T cells expressing a cluster of differentiation 19 protein chimeric antigen receptor (CD19CAR) and constitutively expressing Stat5a, administered in combination. When administered together, the engineered CD4+ and CD8+ T cells synergistically enhance tumor infiltration and retention compared to control CD4+ and CD8+ T cells in hematological cancer. The adoptive transfer method includes ex vivo expansion and genetic engineering of CD4+ and CD8+ T cells by transducing the T cells with SEQ ID NO: 1 or SEQ ID NO: 2.
Claims Coverage
The document includes one independent claim that covers a method of adoptive transfer using ex vivo-expanded, genetically engineered polyfunctional CD4+ and CD8+ T cells expressing CD19CAR and constitutively expressing STAT5A (SEQ ID NO: 1 or 2). The independent claim contains multiple inventive features, including reverse exhaustion, STAT5A-associated epigenetic and expression changes, and synergistic enhancement of tumor infiltration and retention when CD4+ and CD8+ engineered products are administered in combination.
Adoptive transfer of polyfunctional CD4+ and CD8+ CD19CAR T cells constitutively expressing Stat5a
A method comprising isolating CD4+ and CD8+ T cells, expanding them ex vivo, genetically engineering the CD4+ and CD8+ T cells to produce polyfunctional CD4+ and CD8+ T cells that express CD19CAR and constitutively express STAT5A by transducing with SEQ ID NO: 1 or 2, and administering the engineered cells to the subject in an amount effective to induce an immune response to cancer.
Reverse exhaustion in tumor-specific CD4+ and CD8+ T cells
The polyfunctional CD4+ and CD8+ T cells expressing CD19CAR and constitutively expressing STAT5A reverse exhaustion in tumor-specific CD4+ and CD8+ T cells in the subject with hematological cancer.
Constitutive STAT5a activity induces epigenetic and expression changes versus controls
The constitutive STAT5a activity induces epigenetic changes and changes in expression in comparison to control CD4+ and CD8+ T cells in hematological cancer.
Synergistic enhancement of tumor infiltration and retention by combined CD4 and CD8 administration
When the polyfunctional CD4+ and CD8+ T cells expressing CD19CAR and constitutively expressing STAT5A are administered in combination, they synergistically enhance tumor infiltration and retention of CD4+ and CD8+ T cells compared to control CD4+ and CD8+ T cells in hematological cancer.
Overall claim coverage centers on adoptive transfer of ex vivo-expanded, genetically engineered polyfunctional CD4+ and CD8+ T cells expressing CD19CAR and constitutively expressing STAT5A, with performance characteristics including reversal of exhaustion, STAT5A-driven epigenetic and expression changes compared to controls, and synergistic enhancement of tumor infiltration and retention when CD4+ and CD8+ engineered products are administered together.
Stated Advantages
Induces an immune response to cancer in a subject with hematological cancer.
Reverses exhaustion in tumor-specific CD4+ and CD8+ T cells.
Constitutive STAT5a activity induces epigenetic changes and changes in expression compared to control CD4+ and CD8+ T cells.
Synergistically enhances tumor infiltration and retention of CD4+ and CD8+ T cells compared to control T cells.
Documented Applications
Treating a subject with hematological cancer using an adoptive transfer method of polyfunctional CD4+ and CD8+ T cells expressing CD19CAR and constitutively expressing Stat5a.
Treating a hematologic cancer specifically B cell lymphoma using the adoptive transfer method of the engineered polyfunctional CD4+ and CD8+ CD19CAR/STAT5a T cells.
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