Dataset Information

4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2^nd Generation Chimeric Antigen Receptor-Modified T Cells.

ABSTRACT: While chimeric antigen receptor-modified T (CAR-T) cells have shown great success for the treatment of B cell leukemia, their efficacy appears to be compromised in B cell derived lymphoma and solid tumors. Optimization of the CAR design to improve persistence and cytotoxicity is a focus of the current CAR-T study. Herein, we established a novel CAR structure by adding a full length 4-1BB co-stimulatory receptor to a 28Z-based second generation CAR that targets CD20. Our data indicated that this new 2028Z-4-1BB CAR-T cell showed improved proliferation and cytotoxic ability. To further understand the mechanism of action, we found that constitutive 4-1BB sensing significantly reduced the apoptosis of CAR-T cells, enhanced proliferation, and increased NF-?B pathway activation. Consistent with the enhanced proliferation and cytotoxicity in vitro, this new structure of CAR-T cells exhibited robust persistence and anti-tumor activity in a mouse xenograft lymphoma model. This work provides evidence for a new strategy to optimize the function of CAR-T against lymphoma.

SUBMITTER: Dai Q

PROVIDER: S-EPMC7691374 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2<sup>nd</sup> Generation Chimeric Antigen Receptor-Modified T Cells.

Dai Qiang Q Han Ping P Qi Xinyue X Li Fanlin F Li Min M Fan Lilv L Zhang Huihui H Zhang Xiaoqing X Yang Xuanming X

Frontiers in immunology 20201113

While chimeric antigen receptor-modified T (CAR-T) cells have shown great success for the treatment of B cell leukemia, their efficacy appears to be compromised in B cell derived lymphoma and solid tumors. Optimization of the CAR design to improve persistence and cytotoxicity is a focus of the current CAR-T study. Herein, we established a novel CAR structure by adding a full length 4-1BB co-stimulatory receptor to a 28Z-based second generation CAR that targets CD20. Our data indicated that this ...[more]

PMID: 33281809

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Project description:INTRODUCTION:There is no curative treatment available for patients with chemotherapy relapsed or refractory CD19+ B cells-derived acute lymphoblastic leukaemia (r/r B-ALL). Although CD19-targeting second-generation (2nd-G) chimeric antigen receptor (CAR)-modified T cells carrying CD28 or 4-1BB domains have demonstrated potency in patients with advanced B-ALL, these 2 signalling domains endow CAR-T cells with different and complementary functional properties. Preclinical results have shown that third-generation (3rd-G) CAR-T cells combining 4-1BB and CD28 signalling domains have superior activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 domain. The aim of the current study is therefore to investigate the safety and efficacy of 3rd-G CAR-T cells in adults with r/r B-ALL. METHODS AND ANALYSIS:This study is a phase I clinical trial for patients with r/r B-ALL to test the safety and preliminary efficacy of 3rd-G CAR-T cells. Before receiving lymphodepleting conditioning regimen, the peripheral blood mononuclear cells from eligible patients will be leukapheresed, and the T cells will be purified, activated, transduced and expanded ex vivo. On day 6 in the protocol, a single dose of 1 million CAR-T cells per kg will be administrated intravenously. The phenotypes of infused CAR-T cells, copy number of CAR transgene and plasma cytokines will be assayed for 2?years after CAR-T infusion using flow cytometry, real-time quantitative PCR and cytometric bead array, respectively. Moreover, several predictive plasma cytokines including interferon-?, interleukin (IL)-6, IL-8, Soluble Interleukin (sIL)-2R-?, solubleglycoprotein (sgp)130, sIL-6R, Monocyte chemoattractant protein (MCP1), Macrophage inflammatory protein (MIP1)-?, MIP1-? and Granulocyte-macrophage colony-stimulating factor (GM-CSF), which are highly associated with severe cytokine release syndrome (CRS), will be used to forecast CRS to allow doing earlier intervention, and CRS will be managed based on a revised CRS grading system. In addition, patients with grade 3 or 4 neurotoxicities or persistent B-cell aplasia will be treated with dexamethasone (10?mg intravenously every 6?hours) or IgG, respectively. Descriptive and analytical analyses will be performed. ETHICS AND DISSEMINATION:Ethical approval for the study was granted on 10 July 2014 (YLJS-2014-7-10). Written informed consent will be taken from all participants. The results of the study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report. TRIAL REGISTRATION NUMBER:NCT02186860.

Dataset Information

4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2^nd Generation Chimeric Antigen Receptor-Modified T Cells.

Publications

4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2<sup>nd</sup> Generation Chimeric Antigen Receptor-Modified T Cells.

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Dataset Information

4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T Cells.

Publications

4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2<sup>nd</sup> Generation Chimeric Antigen Receptor-Modified T Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2^nd Generation Chimeric Antigen Receptor-Modified T Cells.