Compositions and methods for the isolation and/or generation of specific CD4+ and CD8+ T-cell subsets
Inventors
Cheroutre, Hilde • THIAULT, Nicolas • LARANGE, Alexandre • Iwaya, Hitoshi
Assignees
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Publication Number
US-11951128-B2
Publication Date
2024-04-09
Expiration Date
Abstract
The present disclosure relates to particular subsets of CD4+ and CD8+ T-cells, methods of isolating and generating these cells, compositions comprising these cells, and methods of treatment of a tumor or cancer by administering these cells alone or in combination with each other and/or additional therapies.
Core Innovation
The disclosure relates to tumor immunotherapy using reprogrammed tumor-specific CD4+ cytotoxic T-cells. A population of tumor-specific CD4+ cytotoxic T-cells is generated by contacting tumor-specific CD4+ T-cells with a combination comprising retinoic acid and cytokines, where the cytokines consist of TGF-β and IL-27. This contacting generates tumor-specific CD4+ cytotoxic T-cells for anti-tumor activity.
The described combination can be further refined by including additional cytokines and by defining cytotoxic and reprogrammed phenotypes. The disclosure includes phenotype markers for the reprogrammed cells, including CD4+ ThPOK−, Gata3−/Runx3+, Tbet+, PD-1−, and Lag3−, with an emphasis on CD8αα+ of the CD4+/CD8 fate. Reprogramming is further supported by documented examples showing anti-tumor activity in murine models.
The disclosure also describes methods and compositions for isolating and selecting CD8αα-high cells using TL tetramers, including TL (non-classical MHC class I) tetramer bound CD8αα-high cells, to obtain substantially homogeneous clonal or enriched populations. The overall framework can include engineered T-cells (including CAR T-cells) and can involve immune checkpoint inhibitor contexts, as well as combined or sequential CD8→CD4 approaches with IFNγ-driven MHC class II upregulation in the tumor setting.
Claims Coverage
The independent claims define methods for generating tumor-specific CD4+ cytotoxic T-cells by contacting tumor-specific CD4+ T-cells with defined combinations. The inventive features focus on two independent claim groupings.
Retinoic acid plus TGF-β and IL-27 contacting tumor-specific CD4+ T-cells
Contacting a population of tumor-specific CD4+ T-cells with an effective amount of a combination comprising retinoic acid and cytokines consisting of TGF-β and IL-27, thereby generating tumor-specific CD4+ cytotoxic T-cells.
Anti-CD3 or anti-CD28 stimulation with retinoic acid, TGF-β, and IL-27
Contacting a population of tumor-specific CD4+ T-cells with an effective amount of a combination consisting of retinoic acid, TGF-β, IL-27, and an effective amount of an anti-CD3 or an anti-CD28 antibody, thereby generating tumor-specific CD4+ cytotoxic T-cells.
Across the independent claims, tumor-specific CD4+ cytotoxic T-cells are generated by contacting tumor-specific CD4+ T-cells with retinoic acid together with TGF-β and IL-27, optionally adding antibody-mediated stimulation via anti-CD3 or anti-CD28.
Stated Advantages
Generates tumor-specific CD4+ cytotoxic T-cells for anti-tumor activity.
Documented Applications
Tumor immunotherapy using reprogrammed tumor-specific CD4+ cytotoxic T-cells, including anti-tumor activity in murine models.
Diagnostic/selection use of TL tetramers to identify TL-tetramer bound CD8αα-high cells for obtaining enriched or substantially homogeneous populations.
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