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Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [VDJ-seq]

ABSTRACT: Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [VDJ-seq]

PROVIDER: PRJNA691020 | ENA |

REPOSITORIES: ENA

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Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [VDJ-seq]

Project description:While T cell-based immunotherapies have shown promising clinical responses, current cancer treatments are restricted to autologous cellular products due to the risk of graft-versus-host disease (GvHD) by allogeneic cell transfer. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing off-the-shelf allogeneic cellular therapy because they are powerful immune cells targeting a broad range of cancers without causing GvHD. However, current immunotherapies using iNKT cells are impeded by their extremely low number in cancer patients. In this study, we aimed to overcome this limitation by generating a large number of iNKT cells through TCR engineering of human hematopoietic stem cells (HSCs) and differentiation of HSCs to iNKT cells in an in vitro cultured system. Additionally, Chimeric antigen receptor (CAR) engineering and the CRISPR-Cas9 gene editing tool were utilized to enhance the tumor killing efficacy of iNKT cells and eliminate HLA molecules on their surface, making the cellular product suitable for cancer therapy and allogeneic adoptive transfer. Our results demonstrated successful generation of the promising off-the-shelf B cell maturation antigen (BCMA)-CAR engineered iNKT cells for treating multiple myeloma, and the same strategy will be applied to multiple cellular products for treating other cancers.

2021-12-01 | GSE164500 | GEO

Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [RNA-seq]

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Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy

Project description:Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy

| PRJNA691019 | ENA

Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [RNA-seq]

Project description:Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [RNA-seq]

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Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-12-01 | GSE164501 | GEO

Epigenetic sequencing of allogeneic HSC-derived CAR-engineered NKT cells

Project description:CAR-T cell therapy has achieved remarkable clinical outcomes, yet the autologous nature of FDA-approved CAR-T products present significant challenges in manufacturing, cost, and patient selection. Therefore, there is a growing demand for off-the-shelf cell therapy. Here we introduce an ex vivo feeder-free culture to differentiate gene-engineered HSCs into allogeneic NKT cells, as well as their CAR-armed and IL-15-enhanced derivatives (Allo15CAR-NKT cells). In order to study the epigenetic regulation of the generated cells, we performed DNA methylation sequencing on both IL-15-enhanced and non-IL-15-engineered AlloCAR-NKT cells. Conventional CAR-T cells were included as a control.

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Generation of off-the-shelf CAR-NKT cells for cancer immunotherapy with genetically engineered HSCs and feeder-free differentiation culture

Project description:Current CAR-T cell therapy's clinical potential is hampered by its autologous nature that poses significant challenges in manufacturing, costs, and patient selection. This spurs demand for off-the-shelf therapies. Here we introduce an ex vivo feeder-free culture to differentiate gene-engineered HSCs into allogeneic NKT cells and their CAR-armed derivatives (AlloCAR-NKT cells). The AlloCAR-NKT cells are generated at high yield, purity, and robustness. These cells exhibit potent antitumor efficacy, showing effective tumor homing, clonal expansion, and persistence In vivo. Impressively, AlloCAR-NKT cells can alter the tumor microenvironment by selectively depleting immunosuppressive TAMs and MDSCs, and can antagonize tumor immune evasion by deploying CAR/TCR/NKR triple-targeting mechanisms. AlloCAR-NKT cells also demonstrate an appealing safety profile with low GvHD and CRS risks, and exhibit a stable “hypoimmunogenic” phenotype attributed to epigenetic and signaling regulations. The reported technology presents a scalable strategy for diverse allogeneic CAR-NKT cell products, with potential for clinical translation and commercialization against various cancers.

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