Gemcitabine Synergizes with Immune Checkpoint Inhibitors and Overcomes Resistance in a Preclinical Model and Mesothelioma Patients

Paulino Tallón de Lara; Virginia Cecconi; Stefanie Hiltbrunner; Hideo Yagita; Martina Friess; Beata Bode; Isabelle Opitz; Bart Vrugt; Walter Weder; Paul Stolzmann; Emanuela Felley-Bosco; Rolf A Stahel; Verena Tischler; Christian Britschgi; Davide Soldini; Maries van den Broek; Alessandra Curioni-Fontecedro

doi:10.1158/1078-0432.CCR-18-1231

Gemcitabine Synergizes with Immune Checkpoint Inhibitors and Overcomes Resistance in a Preclinical Model and Mesothelioma Patients

Clin Cancer Res. 2018 Dec 15;24(24):6345-6354. doi: 10.1158/1078-0432.CCR-18-1231. Epub 2018 Aug 28.

Authors

Paulino Tallón de Lara¹, Virginia Cecconi¹, Stefanie Hiltbrunner¹, Hideo Yagita², Martina Friess³, Beata Bode⁴, Isabelle Opitz³, Bart Vrugt⁴, Walter Weder³, Paul Stolzmann⁵, Emanuela Felley-Bosco³, Rolf A Stahel⁶, Verena Tischler⁴, Christian Britschgi⁶, Davide Soldini⁴, Maries van den Broek⁷, Alessandra Curioni-Fontecedro⁸

Affiliations

¹ Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
² Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
³ Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
⁴ Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
⁵ Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland.
⁶ Department of Hematology and Oncology, University Hospital Zurich, Zurich, Switzerland.
⁷ Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. [email protected] [email protected].
⁸ Department of Hematology and Oncology, University Hospital Zurich, Zurich, Switzerland. [email protected] [email protected].

PMID: 30154226
DOI: 10.1158/1078-0432.CCR-18-1231

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 preclinical mesothelioma model; however, the addition of dexamethasone to gemcitabine and immune checkpoint inhibitors nullified the synergistic clinical response. Furthermore, treatment with gemcitabine plus anti-PD-1 resulted in an objective clinical response in two patients with mesothelioma, who were resistant to gemcitabine or anti-PD-1 as monotherapy.

Conclusions: Thus, treatment of mesothelioma with a combination of gemcitabine with immune checkpoint inhibitors is feasible and results in synergistic clinical response compared with single treatment in the absence of steroids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Immunological / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
B7-H1 Antigen / genetics
B7-H1 Antigen / metabolism
Biomarkers, Tumor*
Biopsy
Cell Line, Tumor
Deoxycytidine / analogs & derivatives*
Deoxycytidine / pharmacology
Disease Models, Animal
Drug Resistance, Neoplasm*
Drug Synergism
Gemcitabine
Gene Expression
Humans
Immunomodulation / drug effects*
Lung Neoplasms / diagnosis
Lung Neoplasms / drug therapy
Lung Neoplasms / immunology*
Lung Neoplasms / metabolism
Mesothelioma / diagnosis
Mesothelioma / drug therapy
Mesothelioma / immunology*
Mesothelioma / metabolism
Mesothelioma, Malignant
Mice
Positron Emission Tomography Computed Tomography
Prognosis
Treatment Outcome
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents, Immunological
B7-H1 Antigen
Biomarkers, Tumor
CD274 protein, human
Deoxycytidine
Gemcitabine