Editors' ChoiceImmunotherapy

Toward off-the-shelf adoptive T cell therapies

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Science Translational Medicine  19 Apr 2017:
Vol. 9, Issue 386, eaan2779
DOI: 10.1126/scitranslmed.aan2779

Abstract

Artificial thymic organoids may enable more efficient engineered T cell production for immunotherapy.

T cells that mature in the thymus are the key elements of the body’s natural defenses to combat diseases. Boosting the ability of T cells to fight cancer cells has shown promise for a growing numbers of cancer types. In adoptive cell transfer therapy, T cells isolated from patient blood are genetically engineered in a laboratory to produce specific receptors on their surface, enabling them to better find and destroy cancer cells. To accelerate the development of T cell therapies, it is crucial to establish a robust system that allows researchers to study T cell differentiation and increase T cells production efficiency in vitro.

In their recent study, Seet et al. created artificial thymic organoids that produce human T cells. To form the three-dimensional (3D) organoids, mouse bone marrow stromal cells transduced with human delta-like canonical Notch ligand 1 (DLL1) were aggregated with human hematopoietic stem and progenitor cells (HSPCs) by centrifugation, and the aggregates were cultured using a serum-free medium. Unlike 2D culture systems or previously reported systems, the artificial thymic organoids strongly supported the differentiation and positive selection of mature T cells from HSPCs. Robust T cell differentiation was dependent on three factors: the 3D (as opposed to 2D) organoid structure, the stromal cell line used, and the serum-free medium.

Mature T cells produced by the organoids exhibited key functions of naturally produced T cells, such as a diverse T cell receptor (TCR) repertoire and cytokine production. The artificial thymic organoids could produce naïve, unperturbed antigen-specific T cells without extensive genetic manipulation, which could damage the cell functions. Using the organoid system, the authors produced T cells that are specific to NY-ESO-1, a human tumor antigen. These engineered T cells selectively induced apoptosis in cell lines expressing NY-ESO-1 while showing little activity against cells without NY-ESO-1 expression. Injecting the cancer-specific T cells into cancer-bearing mice significantly slowed cancer progression.

In this study, the authors demonstrated that a 3D thymus organoid culture system could produce engineered T cells with cancer-recognizing receptors but without receptors that could induce off-target effects, which is crucial for the development of off-the-shelf adoptive T cell therapies. The organoid system is highly reproducible and scalable, since it utilizes nonthymic tissue cells and serum-free medium. The simplicity and scalability of the artificial thymic organoid culture system may accelerate the development of engineered T cell therapies.

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