Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response

Our plain-English summary of Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response, by F. Dammeijer, C.J. De Gooijer, M. van Gulijk, et al (EBioMedicine, 2021).

The study

• Authors: F. Dammeijer, C.J. De Gooijer, M. van Gulijk, M. Lukkes, L. Klaase, L.A. Lievense, C. Waasdorp, M. Jebbink, G.P. Bootsma, J.A. Stigt, B. Biesma, M.E.H. Kaijen-Lambers, J. Mankor, H. Vroman, R. Cornelissen, P. Baas, V. Van der Noort, J.A. Burgers, J.G. Aerts
• Journal: EBioMedicine
• Published: 2021;64:103160
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma.

Methods: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS.

Findings: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid-derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4+ T-helper, CD8+ T- and NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS.

Interpretation: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies.

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

In plain English

This study was a predefined exploratory analysis within NVALT19. NVALT19 was a randomized, open-label phase 2 trial in the Netherlands (2014 to 2019) comparing maintenance gemcitabine chemotherapy with best supportive care in malignant mesothelioma patients whose disease had not progressed after first-line chemotherapy. The authors examined blood immune cells at baseline and about three weeks later in 46 patients with malignant pleural mesothelioma: 27 on gemcitabine and 19 on best supportive care. In gemcitabine-treated patients, natural killer (NK) cell proliferation rose, regulatory T-cell proliferation fell, and myeloid-derived suppressor cells (MDSCs) fell. The size of the MDSC drop correlated with T-cell proliferation. The markers ICOS, CD28 and HLA-DR increased on T and NK cells. Cytokine production did not differ statistically between the groups. Among 22 gemcitabine-treated patients, those whose NK-cell proliferation increased had significantly better progression-free and overall survival. A rise in PD-1 on proliferating CD8+ T cells was also associated with better outcome. These links were not seen in the supportive-care group. The authors called the findings exploratory, citing the small cohort and the lack of a validation group. The article does not address asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Predefined exploratory subgroup analysis (blood immune monitoring) within a multicenter, open-label, randomized phase 2 trial (NVALT19)
• Who was studied: 46 malignant pleural mesothelioma patients from the NVALT19 trial (130 patients in total, conducted in the Netherlands 2014 to 2019): 27 received gemcitabine and 19 best supportive care. Both blood cell types (PBMCs and MDSCs) were available for 24 patients. Lymphocyte analyses included 35 patients (22 gemcitabine, 13 best supportive care), MDSC analyses 35 patients (21 gemcitabine, 14 best supportive care), and survival analyses 22 gemcitabine-treated patients.
• Exposure: Maintenance gemcitabine, 1250 mg/m2 on days one and eight of every 21-day cycle, compared with best supportive care, after first-line platinum-pemetrexed chemotherapy. Asbestos exposure was not studied.
• Main results:
  • In gemcitabine-treated patients, NK-cell proliferation increased significantly. In untreated (best supportive care) patients, proliferation of CD8+ T cells and NK cells decreased over time.
  • Proliferation of activated, highly immune-suppressive regulatory T cells (aTregs) decreased following gemcitabine.
  • Neither group showed statistically significant changes in T-cell frequencies or in the distribution of T-cell memory subsets.
  • Gemcitabine significantly reduced MDSCs. The size of the reduction correlated with CD4+ T-helper and CD8+ T-cell proliferation, but not with NK-cell proliferation (correlation calculated in 17 gemcitabine-treated patients).
  • PD-1 increased significantly on CD8+ T cells only in gemcitabine-treated patients. The co-stimulatory markers ICOS, CD28 and HLA-DR increased uniformly on T and NK cells in treated patients.
  • Cytokine production did not differ statistically between treated and untreated patients, although the authors noted a trend toward increased expression with gemcitabine.
  • Among gemcitabine-treated patients, those with an increase in NK-cell proliferation had significantly better progression-free and overall survival. An increase in PD-1 on proliferating (but not total) CD8+ T cells was associated with improved outcome. The hazard ratios are printed in damaged form and are not reproduced here.
  • These parameters did not correlate with clinical outcome in patients on best supportive care, which the authors took as suggesting a gemcitabine-specific response.
• The authors' conclusion: The authors concluded that the findings suggest gemcitabine preferentially activates anti-tumour immune cells and inhibits regulatory T cells and MDSCs. They stated that these pilot data, if validated in larger prospective cohorts, may support development of on-treatment biomarkers.
• Limitations the authors state:
  • The cohort was small and there was no validation group, so the authors stated that formal conclusions cannot be drawn and the results should be considered exploratory.
  • There were no functional in vitro data, so the authors could not pinpoint which cellular mechanisms produced the benefit.
  • Pre- and post-treatment tumour tissue was not available, and changes in circulating blood cells may not reflect what happens in tumours.
  • The cell isolation method did not allow proper counting of cells.
  • Recent first-line chemotherapy, concurrent infection or other comorbidities could have influenced the findings.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Gemcitabine, Chemotherapy, Progression-Free Survival, Cytokine, Biomarker.

Related studies

• Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial — C.J. de Gooijer, V. van der Noort, et al. (2021)
• Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor — S.G. Gray, A.M. Baird, et al. (2012)
• Second-line gemcitabine-based chemotherapy regimens improve overall 3-year survival rate in patients with malignant pleural mesothelioma: a multicenter retrospective study — H. Mutlu, S. Gündüz, et al. (2014)
• Epirubicin and gemcitabine as first-line treatment in malignant pleural mesothelioma — L. Portalone, A. Antilli, et al. (2005)
• Pilot Study to Predict Pharmacokinetics of a Therapeutic Gemcitabine Dose From a Microdose — M. Van Nuland, H. Rosing, et al. (2020)
• A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma — O. Arrieta, D. López-Macías, et al. (2014)

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