Abstract B7: MDSC frequencies in peripheral blood of ipilimumab-treated melanoma patients correlate with clinical response and overall survival.

Abstract

Abstract Background: Metastatic melanoma has a poor prognosis, with high resistance to chemotherapy and irradiation. Recently, immunotherapy has shown clinical efficacy. The anti-CTLA-4 antibody ipilimumab (Yervoy©) was the first agent to significantly prolong the overall survival of stage III/IV melanoma patients, and received FDA approval in March 2011. About 10-13% of patients develop a clinical response during the treatment. A major focus of patient monitoring is to identify biomarkers that predict clinical outcome. We studied Myeloid Derived Suppressor Cells (MDSC) in ipilimumab treated stage III/IV melanoma patients in order to analyze drug-induced changes in the myeloid cell compartment and possible correlations with clinical outcome. Methods: Before and after treatment with ipilimumab, PBMC were isolated by Ficoll gradient centrifugation from fresh blood samples of patients with stage III/IV melanoma. Freshly isolated cells were characterized by multicolor flow cytometry. Results: Lin- CD14+ HLA-DR- monocytic and lin- CD15+ HLA-DR- granulocytic MDSC were enriched in patients, as compared to healthy controls. During ipilimumab treatment, MDSC frequencies remained stable compared to baseline levels, with high patient-to-patient variability. After tumor resection, lin- CD14+ HLA-DR- cells did not change, whereas frequencies of lin- CD15+ HLA-DR- cells decreased. Our data show that frequencies of lin- CD14+ HLA-DR- cells were independent of serum LDH levels, but were significantly enriched in patients with severe metastatic disease (M1c) compared to patients with metastasis in distant skin or lymph nodes only (M1a). Interestingly, clinical responders to ipilimumab treatment showed significantly less lin- CD14+ HLA-DR- cells during and after treatment, compared to non-responders. This difference was found regardless of the metastatic stage. The relevance of low monocytic MDSC levels (less than 1.00%) was further confirmed by the finding that these patients had a significantly prolonged overall survival. Conclusion: Malignant melanoma is associated with increased frequencies of lin- CD14+ HLA-DR-monocytic and lin- CD15+ HLA-DR- granulocytic MDSC. The frequency of monocytic MDSC in ipilimumab treated patients during and after treatment may be used as predictive marker, since low frequencies identify patients that are more likely to benefit from the treatment in terms of tumor regression and prolonged overall survival. Citation Format: Christiane Meyer, Laurene Cagnon, Carla M. Costa Nunes, Petra Baumgaertner, Nicole Montandon, Loredana Leyvraz, Olivier Michielin, Emanuela Romano, Daniel E. Speiser. MDSC frequencies in peripheral blood of ipilimumab-treated melanoma patients correlate with clinical response and overall survival. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B7.