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Efficient derivation of chimeric-antigen receptor-modified T_SCM cells.

ABSTRACT: Chimeric-antigen receptor (CAR) T-cell immunotherapy employs autologous-T cells modified with an antigen-specific CAR. Current CAR-T manufacturing processes tend to yield products dominated by effector T cells and relatively small proportions of long-lived memory T cells. Those few cells are a so-called stem cell memory T (T_SCM) subset, which express naïve T-cell markers and are capable of self-renewal and oligopotent differentiation into effector phenotypes. Increasing the proportion of this subset may lead to more effective therapies by improving CAR-T persistence; however, there is currently no standardized protocol for the effective generation of CAR-T_SCM cells. Here we present a simplified protocol enabling efficient derivation of gene-modified T_SCM cells: Stimulation of naïve CD8+ T cells with only soluble anti-CD3 antibody and culture with IL-7 and IL-15 was sufficient for derivation of CD8+ T cells harboring T_SCM phenotypes and oligopotent capabilities. These in-vitro expanded T_SCM cells were engineered with CARs targeting the HIV-1 envelope protein as well as the CD19 molecule and demonstrated effector activity both in vitro and in a xenograft mouse model. This simple protocol for the derivation of CAR-T_SCM cells may facilitate improved adoptive immunotherapy.

SUBMITTER: Kranz E

PROVIDER: S-EPMC9366550 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Efficient derivation of chimeric-antigen receptor-modified T<sub>SCM</sub> cells.

Kranz Emiko E Kuhlmann Charles J CJ Chan Joshua J Kim Patrick Y PY Chen Irvin S Y ISY Kamata Masakazu M

Frontiers in immunology 20220728

Chimeric-antigen receptor (CAR) T-cell immunotherapy employs autologous-T cells modified with an antigen-specific CAR. Current CAR-T manufacturing processes tend to yield products dominated by effector T cells and relatively small proportions of long-lived memory T cells. Those few cells are a so-called stem cell memory T (T<sub>SCM</sub>) subset, which express naïve T-cell markers and are capable of self-renewal and oligopotent differentiation into effector phenotypes. Increasing the proportion ...[more]

PMID: 35967430

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Project description:Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells in vivo is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype. LEN was shown to increase antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase Cereblon, which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors, which in turn results in changed expression of various receptors on the surface of tumor cells. In order to enhance the effectiveness of CAR-based immunotherapy, we assessed the anti-lymphoma efficacy of LEN in combination with CAR19 T cells or CAR20 T cells in vitro and in vivo using various murine models of aggressive B-cell non-Hodgkin lymphomas (B-NHL).Immunodeficient NSG mice were transplanted with various human B-NHL cells followed by treatment with CAR19 or CAR20 T cells with or without LEN. Next, CAR19 T cells were subjected to series of tests in vitro to evaluate their response and signaling capacity following recognition of B cell in the presence or absence of LEN.Our data shows that LEN significantly enhances antitumor functions of CAR19 and CAR20 T cells in vivo. Additionally, it enhances production of interferon gamma by CAR19 T cells and augments cell signaling via CAR19 protein in T cells in vitro. Our data further suggests that LEN works through direct effects on T cells but not on B-NHL cells. The biochemical events underlying this costimulatory effect of LEN are currently being investigated. In summary, our data supports the use of LEN for augmentation of CAR-based immunotherapy in the clinical grounds.

Dataset Information

Efficient derivation of chimeric-antigen receptor-modified T_SCM cells.

Publications

Efficient derivation of chimeric-antigen receptor-modified T<sub>SCM</sub> cells.

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Dataset Information

Efficient derivation of chimeric-antigen receptor-modified TSCM cells.

Publications

Efficient derivation of chimeric-antigen receptor-modified T<sub>SCM</sub> cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Efficient derivation of chimeric-antigen receptor-modified T_SCM cells.