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Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth

BACKGROUND: Small cell lung cancer (SCLC) accounts for 15% of lung cancers, and the primary treatment of this malignancy is chemotherapy and radiotherapy. Delta-like 3 (DLL3) is an attractive target for SCLC immunotherapy since its expression is highly restricted to SCLC with a neglectable appearanc...

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Autores principales: Chen, Xin, Amar, Norhan, Zhu, Yuankui, Wang, Chunguang, Xia, Chunjiao, Yang, Xiaoqing, Wu, Dongde, Feng, Mingqian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304844/
https://www.ncbi.nlm.nih.gov/pubmed/32554616
http://dx.doi.org/10.1136/jitc-2020-000785
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author Chen, Xin
Amar, Norhan
Zhu, Yuankui
Wang, Chunguang
Xia, Chunjiao
Yang, Xiaoqing
Wu, Dongde
Feng, Mingqian
author_facet Chen, Xin
Amar, Norhan
Zhu, Yuankui
Wang, Chunguang
Xia, Chunjiao
Yang, Xiaoqing
Wu, Dongde
Feng, Mingqian
author_sort Chen, Xin
collection PubMed
description BACKGROUND: Small cell lung cancer (SCLC) accounts for 15% of lung cancers, and the primary treatment of this malignancy is chemotherapy and radiotherapy. Delta-like 3 (DLL3) is an attractive target for SCLC immunotherapy since its expression is highly restricted to SCLC with a neglectable appearance on normal adult tissues. In the current study, we aimed to explore the efficacy of DLL3-targeted SCLC immunotherapy via the engagement of T cell. METHODS: As a proof of concept, we constructed DLL3-targeted bispecific antibody and chimeric antigen receptor (CAR)-modified T cells. In vitro and in vivo tumor-suppression activity of these treatments alone or in combination with a Program Death-1 (PD-1) inhibitory antibody was evaluated. RESULTS: In vitro studies showed that both DLL3 bispecific antibody and CAR-T efficiently killed DLL3-positive cancer cells, including the native SCLC cell lines H446, H196, H82, and the artificial A431 cells that were forcefully overexpressing DLL3. In vivo studies in xenograft mouse models demonstrated that both bispecific antibody and CAR-T suppressed the tumor growth, and combination therapy with PD-1 inhibitory antibody dramatically improved the efficacy of the DLL3 bispecific antibody, but not the CAR-T cells. CONCLUSIONS: Our results demonstrated that DLL3-targeted bispecific antibody plus PD-1 inhibition was effective in controlling SCLC growth.
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spelling pubmed-73048442020-06-22 Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth Chen, Xin Amar, Norhan Zhu, Yuankui Wang, Chunguang Xia, Chunjiao Yang, Xiaoqing Wu, Dongde Feng, Mingqian J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Small cell lung cancer (SCLC) accounts for 15% of lung cancers, and the primary treatment of this malignancy is chemotherapy and radiotherapy. Delta-like 3 (DLL3) is an attractive target for SCLC immunotherapy since its expression is highly restricted to SCLC with a neglectable appearance on normal adult tissues. In the current study, we aimed to explore the efficacy of DLL3-targeted SCLC immunotherapy via the engagement of T cell. METHODS: As a proof of concept, we constructed DLL3-targeted bispecific antibody and chimeric antigen receptor (CAR)-modified T cells. In vitro and in vivo tumor-suppression activity of these treatments alone or in combination with a Program Death-1 (PD-1) inhibitory antibody was evaluated. RESULTS: In vitro studies showed that both DLL3 bispecific antibody and CAR-T efficiently killed DLL3-positive cancer cells, including the native SCLC cell lines H446, H196, H82, and the artificial A431 cells that were forcefully overexpressing DLL3. In vivo studies in xenograft mouse models demonstrated that both bispecific antibody and CAR-T suppressed the tumor growth, and combination therapy with PD-1 inhibitory antibody dramatically improved the efficacy of the DLL3 bispecific antibody, but not the CAR-T cells. CONCLUSIONS: Our results demonstrated that DLL3-targeted bispecific antibody plus PD-1 inhibition was effective in controlling SCLC growth. BMJ Publishing Group 2020-06-17 /pmc/articles/PMC7304844/ /pubmed/32554616 http://dx.doi.org/10.1136/jitc-2020-000785 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Clinical/Translational Cancer Immunotherapy
Chen, Xin
Amar, Norhan
Zhu, Yuankui
Wang, Chunguang
Xia, Chunjiao
Yang, Xiaoqing
Wu, Dongde
Feng, Mingqian
Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth
title Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth
title_full Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth
title_fullStr Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth
title_full_unstemmed Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth
title_short Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth
title_sort combined dll3-targeted bispecific antibody with pd-1 inhibition is efficient to suppress small cell lung cancer growth
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304844/
https://www.ncbi.nlm.nih.gov/pubmed/32554616
http://dx.doi.org/10.1136/jitc-2020-000785
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