A Clinical Study of Biomarkers to Predict the Efficacy of Cancer Immunotherapy with Subcutaneous Low-Dose Il-2 or with Immune Checkpoint Inhibitors

Institute of Biological Medicine, Milan, Italy

Corresponding author: Paolo Lissoni, Institute of Biological Medicine, Milan, Italy

Received: February 22, 2019
Published: March 14, 2019

ABSTRACT

The recent advances in the knowledge of the mechanisms involved in the antitumor immunity have allowed to elaborate immunotherapeutic strategies of cancer not only on the basis of an empiristic approach, as well as in the past years but on a better definition of the physiopathology of the anticancer immune response. In particular, it has been demonstrated that the antitumor immunity is mainly mediated  by lymphocytes and that their functional status depends on the expression of specific cell-surface molecules, the so-called immune checkpoints, whose expression  may block T cell activation, the most important of them would be represented by PD-1 and its ligands, PD-L1 and PD-L2. Lymphocyte functions may be activated by IL-2, whereas the action of checkpoints may be blocked by specific anti-PD-1 monoclonal antibodies (MABs). Even though there are controversial results, the efficacy of anti-PD-1 MABs would be related to the expression of PD-L1 by tumor cells or at tumor microenvironment sites, whereas at present no patient-related biological response has been identified to predict the efficacy of anti-PD-1 MABs, whereas that of IL-2 immunotherapy may be predicted by the evidence of an important increase in lymphocyte count in association with a low macrophage system activation. Finally, recent observations have demonstrated that the interactions between lymphocyte and macrophage systems may be reflected by the simple lymphocyte-to-monocyte ratio (LMR) and that the evidence of an abnormally low LMR predicts a poor prognosis. The present study was performed to evaluate the relation between the efficacy of the anti-PD-1 MAB Nivolumab and patient biological response, as investigated by detecting lymphocyte, monocyte, eosinophil counts and LMR, in metastatic non-small cell lung cancer (NSCLC), by comparing the results to those obtained by SC low-dose IL-2. The study included 30 patients treated with Nivolumab and 20 patients treated with IL-2. Patients were evaluated before and after 3 months of immunotherapy. Nivolumab was intravenously administered at  3 mg/kg b.w. At 15-day intervals. IL-2 was injected subcutaneously at a dose of 6 MIU/day for 5 days/week for 4 consecutive weeks, followed by 2 week-rest period. No significant differences in the percentages of both tumor regression and stable disease were seen between patients treated by Nivolumab or IL-2. Irrespectively of the clinical response, mean values of both lymphocytes and eosinophils significantly increased on IL-2 therapy. Monocyte mean count decreased on IL-2 therapy, without, however, significant differences. On the contrary, an increase in lymphocyte and eosinophil mean counts and a decline in monocyte number occurred in the only patients with tumor regression or stable disease under Nivolumab therapy, even though the difference was not significant. In contrast, a significant increase in LMR mean values were observed in patients of Nivolumab group, who achieved a disease control on therapy. This preliminary study would suggest that the increase in LMR may represent a biomarker able to predict the efficacy of anti-PD-1 immunotherapies, while lymphocytosis constitutes the most important favorable prognostic biomarker on IL-2immunotherapy.

Keywords: Checkpoint inhibitors, Immune checkpoints, Immunotherapy, interleukin-2, Nivolumab, Programmed Death-1 (PD-1), PD-L1.