Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

Abstract

Moreover, either the absence or the presence of soluble NKG2D ligands (ULBP-1 or ¡2) at baseline in the serum of MM patients enabled to discriminate subjects with long-term survival (median overall survival, (OS) D 33.6 mo for ULBP-1 and ¡2) from poor survivors (OS D 9.8 or 6.6 mo, respectively). Conversely, no significant association between the levels of soluble MICA, MICB and ULBP-3 and the clinical outcome of patients was observed. An inverse correlation between circulating levels of these molecules at baseline and frequency of either CD3 C CD4 C CD45RO C BTLA C or Th17 or CD3 C CD4 C 4-1BB C T cells occurred in patients with a favorable clinical outcome. The simultaneous monitoring of different immune parameters, though validation in a large cohort of patients is needed, allowed to identify an association between phenotypic and soluble markers representing a possible predictive immunological signature for the clinical activity of IPI plus FTM.

Soluble NKG2D ligands are biomarkers associated with the clinical outcome to immune checkpoint blockade therapy of metastatic melanoma patients

“…We have described previously the role of ULBP-1 and -2 as candidate predictive markers for the clinical outcome of melanoma patients with metastatic disease treated with ipilimumab and fotemustine (NIBIT-M1 study). 25 These findings are substantiated by the present study that evaluated patients treated with immune checkpoint blockade both as monotherapy and in combination. In this study, we also evaluated a cohort of melanoma patients treated with standard therapies or BRAFi.…”

“…The levels of sNKG2DLs were heterogeneous with peak of concentration, except for ULBP-2, lower as compared with patients treated with immunotherapy. Serum levels of sNKG2DLs from patients treated with ipilimumab plus chemotherapy (NIBIT-M1 study; N D 37) that have been described previously, 25 were also included in the subsequent analyses.…”

“…This analysis included also melanoma patients treated with the combination of anti-CTLA-4 and fotemustine (N D 37, see Table 1) for which the levels of sNKG2DLs and the modulation during treatment have been previously reported. 25 Disease control (DC) and OS information were available for N D 193 and 194 patients, respectively.…”

“…These melanoma patients have been treated with (i) ipilimumab at 3 or 10 mg/kg in the context of expanded access programs (EAP) or, more recently, as "on-label usage"; (N D 132); (ii) pembrolizumab for patients previously treated with ipilimumab (N D 15); (iii) monotherapy with ipilimumab or nivolumab or their combination (N D 15). Moreover, patients treated with ipilimumab plus chemotherapy (NIBIT-M1 study; N D 37) that have been described previously, 25 were included in this study to carry out a more extensive evaluation. A control group of melanoma patients included subjects with metastatic disease treated either with standard chemotherapy or radiotherapy regimens (N D 31) or with BRAF inhibitor (BRAFi; vemurafenib; or dabrafenib) -based targeted therapies (N D 34).…”

“…24 We recently showed that the baseline serum levels of soluble NKG2D ligands (sNKG2DLs) can discriminate melanoma patients treated with the combination of ipilimumab plus chemotherapy who experience poor clinical outcome from those with long-term survival. 25 The aim of this study was to assess the value of serum levels of sNKG2DLs as predictors of responsiveness in melanoma patients undergoing immunotherapy regimens. We determined sNKG2DLs levels in pre-and post-treatment sera of melanoma patients treated with immune checkpoint blockade (anti-CTLA-4 or anti-PD-1 mAb monotherapy or their combinations) and the results were correlated with patients' (N D 194) clinical outcome.…”