Blood Predictive Biomarkers for Patients With Non-small-cell Lung Cancer Associated With Clinical Response to Nivolumab

Clin Lung Cancer. 2020 Jan;21(1):75-85. doi: 10.1016/j.cllc.2019.08.006. Epub 2019 Aug 30.

Abstract

Background: Immunotherapy is a promising cancer treatment, but surrogate biomarkers of clinical efficacy have not been fully validated. The aim of this work was to evaluate several biomarkers as predictors of response to nivolumab monotherapy in patients with non-small-cell lung cancer.

Patients and methods: Blood samples was collected at baseline, at 2 months after treatment start, and at disease progression. Lactate dehydrogenase level (LDH), neutrophils, and leukocyte values were obtained from medical record. Interleukin (IL)-8, IL-11, and kynurenine/tryptophan levels were determined by enzyme-linked immunosorbent assay. Total protein was extracted from circulating CD8+ T cells, and BCL-2 interacting mediator of cell death (BIM) protein expression tested by western blotting.

Results: Baseline LDH levels were significantly higher in non-responder patients than in those who responded (P = .045). The increase in indoleamine 2,3 dioxygenase activity was related to progression of disease, mainly in patients who did not respond to nivolumab treatment (P = .001). Increased levels of circulating IL-8 were observed in initially responding patients at time of progression, and it was related to lower overall survival (hazard ratio, 7.49; P = .025). A highest expression of BIM in circulating CD8+ T cells could be related to clinical benefit. The Student t test and Mann-Whitney U test were used to compare groups for continuous variables. Time to events was estimated using the Kaplan-Meier method, and compared by the log-rank test.

Conclusions: Changes in plasma LDH and IL-8, indoleamine 2,3 dioxygenase activity, and BIM expression in CD8+ T cells could be used to monitor and predict clinical benefit from nivolumab treatment in these patients.

Keywords: Biochemical changes in tumor progression; Clinical efficacy; Immune checkpoint inhibitors; Non-invasive quantification of tumour biomarkers; Outcomes in immunotherapy-treated patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Immunological / therapeutic use*
  • Bcl-2-Like Protein 11 / blood
  • Biomarkers, Tumor / blood*
  • CD8-Positive T-Lymphocytes / pathology
  • Carcinoma, Non-Small-Cell Lung / blood
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Female
  • Humans
  • Hydro-Lyases / blood
  • Immunotherapy / methods*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / blood
  • Interleukin-8 / metabolism
  • Lung Neoplasms / blood
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology*
  • Male
  • Middle Aged
  • Nivolumab / therapeutic use*
  • Survival Rate
  • Treatment Outcome

Substances

  • Antineoplastic Agents, Immunological
  • Bcl-2-Like Protein 11
  • Biomarkers, Tumor
  • CXCL8 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interleukin-8
  • indoleamine 2,3-dioxygenase 1, human
  • Nivolumab
  • Hydro-Lyases
  • lactate dehydratase