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... Show moreBackground: 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(+) Tand 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. (C) 2020 The Authors. Published by Elsevier B.V. Show less
Dumoulin, D.W.; Visser, S.; Cornelissen, R.; Gelder, T. van; Vansteenkiste, J.; Thusen, J. von der; Aerts, J.G.J.V. 2020
The combination of chemotherapy and immune check-point inhibition (ICI) therapy is the current standard of care for most patients who are fit to undergo treatment for metastatic NSCLC. With this... Show moreThe combination of chemotherapy and immune check-point inhibition (ICI) therapy is the current standard of care for most patients who are fit to undergo treatment for metastatic NSCLC. With this combination, renal toxicity was slightly higher than with chemotherapy alone in initial clinical trials. However, in recent real-world data, loss of kidney function is reported to be more frequent. Both chemotherapy and ICI therapy can induce renal impairment, although the mechanism of renal damage is different. Renal injury from chemo-therapy is often ascribed to acute tubular injury and necrosis, whereas the main mechanism of injury caused by ICI therapy is acute tubulointerstitial nephritis. In cases of concomitant use of chemotherapy and ICI therapy, distinguishing the cause of renal failure is a challenge. Discriminating between these two causes is of utmost importance, as it would help assess which drug can be safely continued and which drug must be halted. This review aims to describe the underlying mecha-nisms of the renal adverse effects caused by chemo-therapy and ICI therapy, leading to a suggested diagnostic and treatment algorithm on the basis of clinical, laboratory, radiographic, and pathologic param-eters. This algorithm could serve as a supportive tool for clinicians to diagnose the underlying cause of acute kidney injury in patients treated with the combination of chemotherapy and immunotherapy. Show less
