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

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 24 Pg. 6345-6354 (12 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 30154226 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

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

Topics

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