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Rational combination of immunotherapies with clinical efficacy in mice with advanced cancer


Bransi, Ali; Salgado, Oscar Camilo; Beffinger, Michal; Milo, Karim; Silina, Karina; Yagita, Hideo; Becher, Burkhard; Knuth, Alexander; van den Broek, Maries (2015). Rational combination of immunotherapies with clinical efficacy in mice with advanced cancer. Cancer immunology research, 3(11):1279-1288.

Abstract

In the context of cancer, naïve T cells are insufficiently primed and become progressively dysfunctional. Boosting antitumor responses by blocking PD-1 or CTLA-4 results in durable clinical responses only in a limited proportion of cancer patients, suggesting that other pathways must be targeted to improve clinical efficacy. Our preclinical study in TRAMP mice comparing 14 different immune interventions identified anti-CD40 + IL2/anti-IL2 complexes + IL12Fc as a uniquely efficacious treatment that prevents tolerance induction, promotes priming of sustained, protective tumor-specific CD8(+) T cells, and cures late-stage cancer when given together with adoptively transferred tumor-specific T cells. We propose that improving signals 2 (costimulation) and 3 (cytokines) together with fresh tumor-specific, rather than boosting of dysfunctional preexisting memory, T cells represents a potent therapy for advanced cancer. Cancer Immunol Res; 3(11); 1279-88. ©2015 AACR.

Abstract

In the context of cancer, naïve T cells are insufficiently primed and become progressively dysfunctional. Boosting antitumor responses by blocking PD-1 or CTLA-4 results in durable clinical responses only in a limited proportion of cancer patients, suggesting that other pathways must be targeted to improve clinical efficacy. Our preclinical study in TRAMP mice comparing 14 different immune interventions identified anti-CD40 + IL2/anti-IL2 complexes + IL12Fc as a uniquely efficacious treatment that prevents tolerance induction, promotes priming of sustained, protective tumor-specific CD8(+) T cells, and cures late-stage cancer when given together with adoptively transferred tumor-specific T cells. We propose that improving signals 2 (costimulation) and 3 (cytokines) together with fresh tumor-specific, rather than boosting of dysfunctional preexisting memory, T cells represents a potent therapy for advanced cancer. Cancer Immunol Res; 3(11); 1279-88. ©2015 AACR.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:November 2015
Deposited On:11 Dec 2015 14:06
Last Modified:05 Apr 2016 19:36
ISSN:2326-6074
Publisher DOI:https://doi.org/10.1158/2326-6066.CIR-15-0103-T
PubMed ID:26141620

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