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Gemcitabine synergizes with immune checkpoint inhibitors and overcomes resistance in a preclinical model and mesothelioma patients


Tallon de Lara, Paulino; Cecconi, Virginia; Hiltbrunner, Stefanie; Yagita, Hideo; Friess, Martina; Bode-Lesniewska, Beata; Opitz, Isabelle; Vrugt, Bart; Weder, Walter; Stolzmann, Paul; Felley-Bosco, Emanuela; Stahel, Rolf A; Tischler, Verena; Britschgi, Christian; Soldini, Davide; van den Broek, Maries; Curioni Fontecedro, Alessandra (2018). Gemcitabine synergizes with immune checkpoint inhibitors and overcomes resistance in a preclinical model and mesothelioma patients. Clinical Cancer Research, 24(24):6345-6354.

Abstract

PURPOSE Combination of immune checkpoint inhibitors with chemotherapy is under investigation for cancer treatment. EXPERIMENTAL DESIGN We studied the rationale of such a combination for treating mesothelioma, a disease with limited treatment options. RESULTS The combination of gemcitabine and immune checkpoint inhibitors outperformed immunotherapy alone with regard to tumor control and survival in a pre-clinical mesothelioma model; however, the addition of dexamethasone to gemcitabine and immune checkpoint inhibitors nullified the synergistic clinical response. Further, treatment with gemcitabine plus anti-PD-1 resulted in an objective clinical response in two mesothelioma patients, who were resistant to gemcitabine or anti-PD-1 as monotherapy. CONCLUSION Thus, treatment of mesothelioma with a combination of gemcitabine with immune checkpoint inhibitors is feasible and results in synergistic clinical response compared to single treatment in the absence of steroids.

Abstract

PURPOSE Combination of immune checkpoint inhibitors with chemotherapy is under investigation for cancer treatment. EXPERIMENTAL DESIGN We studied the rationale of such a combination for treating mesothelioma, a disease with limited treatment options. RESULTS The combination of gemcitabine and immune checkpoint inhibitors outperformed immunotherapy alone with regard to tumor control and survival in a pre-clinical mesothelioma model; however, the addition of dexamethasone to gemcitabine and immune checkpoint inhibitors nullified the synergistic clinical response. Further, treatment with gemcitabine plus anti-PD-1 resulted in an objective clinical response in two mesothelioma patients, who were resistant to gemcitabine or anti-PD-1 as monotherapy. CONCLUSION Thus, treatment of mesothelioma with a combination of gemcitabine with immune checkpoint inhibitors is feasible and results in synergistic clinical response compared to single treatment in the absence of steroids.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Nuclear Medicine
04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology and Hematology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Thoracic Surgery
04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:15 December 2018
Deposited On:26 Oct 2018 10:58
Last Modified:26 Oct 2019 07:05
Publisher:American Association for Cancer Research
ISSN:1078-0432
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/1078-0432.CCR-18-1231
PubMed ID:30154226

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