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4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2(nd) Generation Chimeric Antigen Receptor-Modified T Cells
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 curre...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691374/ https://www.ncbi.nlm.nih.gov/pubmed/33281809 http://dx.doi.org/10.3389/fimmu.2020.539654 |
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author | Dai, Qiang Han, Ping Qi, Xinyue Li, Fanlin Li, Min Fan, Lilv Zhang, Huihui Zhang, Xiaoqing Yang, Xuanming |
author_facet | Dai, Qiang Han, Ping Qi, Xinyue Li, Fanlin Li, Min Fan, Lilv Zhang, Huihui Zhang, Xiaoqing Yang, Xuanming |
author_sort | Dai, Qiang |
collection | PubMed |
description | 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-κB 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. |
format | Online Article Text |
id | pubmed-7691374 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-76913742020-12-04 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2(nd) Generation Chimeric Antigen Receptor-Modified T Cells Dai, Qiang Han, Ping Qi, Xinyue Li, Fanlin Li, Min Fan, Lilv Zhang, Huihui Zhang, Xiaoqing Yang, Xuanming Front Immunol Immunology 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-κB 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. Frontiers Media S.A. 2020-11-13 /pmc/articles/PMC7691374/ /pubmed/33281809 http://dx.doi.org/10.3389/fimmu.2020.539654 Text en Copyright © 2020 Dai, Han, Qi, Li, Li, Fan, Zhang, Zhang and Yang http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Dai, Qiang Han, Ping Qi, Xinyue Li, Fanlin Li, Min Fan, Lilv Zhang, Huihui Zhang, Xiaoqing Yang, Xuanming 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2(nd) Generation Chimeric Antigen Receptor-Modified T Cells |
title | 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2(nd) Generation Chimeric Antigen Receptor-Modified T Cells |
title_full | 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2(nd) Generation Chimeric Antigen Receptor-Modified T Cells |
title_fullStr | 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2(nd) Generation Chimeric Antigen Receptor-Modified T Cells |
title_full_unstemmed | 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2(nd) Generation Chimeric Antigen Receptor-Modified T Cells |
title_short | 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2(nd) Generation Chimeric Antigen Receptor-Modified T Cells |
title_sort | 4-1bb signaling boosts the anti-tumor activity of cd28-incorporated 2(nd) generation chimeric antigen receptor-modified t cells |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691374/ https://www.ncbi.nlm.nih.gov/pubmed/33281809 http://dx.doi.org/10.3389/fimmu.2020.539654 |
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