Combined treatment with bevacizumab and standard chemotherapy restores abnormal immune parameters in advanced colorectal cancer patients

Invest New Drugs. 2012 Feb;30(1):395-402. doi: 10.1007/s10637-010-9533-0. Epub 2010 Sep 7.

Abstract

Background: Bevacizumab, a monoclonal antibody (mAb) targeting vascular endothelial growth factor (VEGF), has produced promising results when combined with chemotherapy in the treatment of advanced colorectal cancer (CRC). The aim of the present study was to define the immunological profile of metastatic CRC patients at baseline and following chemotherapy with either irinotecan/5-fluorouracil/leucovorin (IFL) alone or IFL in combination with.bevacizumab (B-IFL).

Methods: Peripheral blood mononuclear cells (PBMCs) obtained from healthy donors (HD) (n = 20) and patients (n = 40) were tested for T-cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR), and cytokine production following stimulation with anti-CD3 mAb.

Results: PBMCs obtained from CRC patients prior to treatment exhibited lower auto-MLR responses and low production of IL-2, IFN-γ, IL-12 and IL-18 cytokines, whereas IL-4 and IL-10 cytokines were increased as compared to HD (p < 0.001, for all parameters) following in vitro stimulation with anti-CD3 mAb. During treatment, and in particular in week 12 of evaluation, IL-2 (p < 0.001 for both IFL and B-IFL groups), IFN-γ (p < 0.001 for IFL and p = 0.001 for B-IFL), IL-12 (p < 0.001 for both IFL and B-IFL) and IL-18 (p < 0.001 for both IFL and B-IFL) production, as well as auto-MLR responses increased (p < 0.001 for both IFL and B-IFL), whereas IL-4 (p < 0.001 for IFL and p = 0.001 for B-IFL) and IL-10 [p < 0.001 for IFL and p = 0.067 (non-significant) for B-IFL] production decreased over baseline in the two treatment groups, yet their respective values never reached those of HD. Moreover, IL-2, IFN-γ production, and auto-MLR were higher in the B-IFL over the IFL treatment group (p < 0.001, p < 0.04, p < 0.001, respectively).

Conclusion: Our study demonstrates that the abnormal immune parameters observed in metastatic CRC patients at presentation can substantially improve during treatment with either IFL or B-IFL. The immune parameters examined can provide a sensitive and valuable tool for monitoring immune function in CRC patients, and could be applied as surrogate markers predicting treatment-related outcome.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Aged
  • Angiogenesis Inhibitors / administration & dosage
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / secondary
  • Cytokines / metabolism
  • Female
  • Fluorouracil / administration & dosage
  • Greece
  • Humans
  • Irinotecan
  • Leucovorin / administration & dosage
  • Lymphocyte Culture Test, Mixed
  • Male
  • Middle Aged
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Time Factors
  • Treatment Outcome

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal, Humanized
  • Cytokines
  • Bevacizumab
  • Irinotecan
  • Leucovorin
  • Fluorouracil
  • Camptothecin