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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...

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Autores principales: Dai, Qiang, Han, Ping, Qi, Xinyue, Li, Fanlin, Li, Min, Fan, Lilv, Zhang, Huihui, Zhang, Xiaoqing, Yang, Xuanming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
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.
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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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