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Tumor Regression and Cure Depends on Sustained Th1 Responses

While immunomodulatory monoclonal antibodies (mAbs) have therapeutic efficacy against many tumors, few patients are cured. Attempting to improve their therapeutic efficacy we have applied the TC1 mouse lung carcinoma model and injected established subcutaneous tumors intratumorally with 3 weekly dos...

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Autores principales: Dai, Min, Hellstrom, Ingegerd, Yip, Yuen Y., Sjögren, Hans Olov, Hellstrom, Karl Erik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133214/
https://www.ncbi.nlm.nih.gov/pubmed/29912725
http://dx.doi.org/10.1097/CJI.0000000000000231
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author Dai, Min
Hellstrom, Ingegerd
Yip, Yuen Y.
Sjögren, Hans Olov
Hellstrom, Karl Erik
author_facet Dai, Min
Hellstrom, Ingegerd
Yip, Yuen Y.
Sjögren, Hans Olov
Hellstrom, Karl Erik
author_sort Dai, Min
collection PubMed
description While immunomodulatory monoclonal antibodies (mAbs) have therapeutic efficacy against many tumors, few patients are cured. Attempting to improve their therapeutic efficacy we have applied the TC1 mouse lung carcinoma model and injected established subcutaneous tumors intratumorally with 3 weekly doses of various combinations of mAbs. Combinations of mAbs to CTLA4/PD1/CD137 (the 3 mAb combination) and to CTLA4/PD1/CD137/CD19 (the 4 mAb combination) were most efficacious to induce complete regression of both the injected tumor and an untreated tumor in the same mouse. Tumor cure was consistently associated with shifting a Th2 to a Th1 response in tumor-draining lymph nodes and spleen and it involved epitope specific and long-lived memory T cells as well as M1 macrophages. This shift and accompanying tumor rejection was harder to achieve as the treated tumors increased in size. Relapse of tumors which had initially regressed following treatment with immunomodulatory mAbs was associated with return of a Th2 microenvironment in tumors, tumor-draining lymph nodes and spleens rather than the emergence of immune-resistant tumor cells. While mAbs to CTLA4 plus PD-1 were therapeutically ineffective, combining the 2 of them with intraperitoneal cisplatin, 10 mg/kg, induced long-term complete tumor regression in most mice with small TC1 tumors and the therapeutic efficacy against larger tumors improved by administrating cisplatin together with the 3 or 4 mAb combination.
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spelling pubmed-61332142018-09-20 Tumor Regression and Cure Depends on Sustained Th1 Responses Dai, Min Hellstrom, Ingegerd Yip, Yuen Y. Sjögren, Hans Olov Hellstrom, Karl Erik J Immunother Basic Studies While immunomodulatory monoclonal antibodies (mAbs) have therapeutic efficacy against many tumors, few patients are cured. Attempting to improve their therapeutic efficacy we have applied the TC1 mouse lung carcinoma model and injected established subcutaneous tumors intratumorally with 3 weekly doses of various combinations of mAbs. Combinations of mAbs to CTLA4/PD1/CD137 (the 3 mAb combination) and to CTLA4/PD1/CD137/CD19 (the 4 mAb combination) were most efficacious to induce complete regression of both the injected tumor and an untreated tumor in the same mouse. Tumor cure was consistently associated with shifting a Th2 to a Th1 response in tumor-draining lymph nodes and spleen and it involved epitope specific and long-lived memory T cells as well as M1 macrophages. This shift and accompanying tumor rejection was harder to achieve as the treated tumors increased in size. Relapse of tumors which had initially regressed following treatment with immunomodulatory mAbs was associated with return of a Th2 microenvironment in tumors, tumor-draining lymph nodes and spleens rather than the emergence of immune-resistant tumor cells. While mAbs to CTLA4 plus PD-1 were therapeutically ineffective, combining the 2 of them with intraperitoneal cisplatin, 10 mg/kg, induced long-term complete tumor regression in most mice with small TC1 tumors and the therapeutic efficacy against larger tumors improved by administrating cisplatin together with the 3 or 4 mAb combination. Lippincott Williams & Wilkins 2018-10 2018-06-15 /pmc/articles/PMC6133214/ /pubmed/29912725 http://dx.doi.org/10.1097/CJI.0000000000000231 Text en Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/) (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Basic Studies
Dai, Min
Hellstrom, Ingegerd
Yip, Yuen Y.
Sjögren, Hans Olov
Hellstrom, Karl Erik
Tumor Regression and Cure Depends on Sustained Th1 Responses
title Tumor Regression and Cure Depends on Sustained Th1 Responses
title_full Tumor Regression and Cure Depends on Sustained Th1 Responses
title_fullStr Tumor Regression and Cure Depends on Sustained Th1 Responses
title_full_unstemmed Tumor Regression and Cure Depends on Sustained Th1 Responses
title_short Tumor Regression and Cure Depends on Sustained Th1 Responses
title_sort tumor regression and cure depends on sustained th1 responses
topic Basic Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133214/
https://www.ncbi.nlm.nih.gov/pubmed/29912725
http://dx.doi.org/10.1097/CJI.0000000000000231
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