Pretreatment Serum VEGF Is Associated with Clinical Response and Overall Survival in Advanced Melanoma Patients Treated with Ipilimumab

Abstract

Ipilimumab, an antibody that blocks cytotoxic T lymphocyte antigen 4 (CTLA-4), improves overall survival (OS) for patients with metastatic melanoma. Given its role in angiogenesis and immune evasion, serum vascular endothelial growth factor (VEGF) levels were evaluated for association with clinical benefit in ipilimumab-treated patients. Sera were collected from 176 patients treated at 3 (n=98) or 10 mg/kg (n=68). The VEGF levels before treatment and at induction completion (week 12) were analyzed using the Meso Scale Discovery kit. The association of the levels of VEGF with clinical responses and overall survival (OS) were assessed using the Fisher’s exact and Kaplan-Meier log-rank tests. VEGF as a continuous variable was associated with overall survival (p=0.002). Using 43 pg/ml as the cutoff pre-treatment VEGF value defined by maximally selected log-rank statistics, pretreatment VEGF values correlated with clinical benefit at week 24 (p=0.019; 159 patients evaluable). Pretreatment VEGF ≥ 43 pg/ml was associated with decreased OS (Median OS 6.6 vs. 12.9 months, p=0.006; 7.4 vs. 14.3 months, p=0.037 for 3 mg/kg; 6.2 vs. 10.9 months, p=0.048 for 10 mg/kg). There was no correlation between VEGF changes and clinical outcome. Serum VEGF may be a predictive biomarker for ipilimumab treatment, and is worthy of prospective investigation with various forms of immunologic checkpoint blockade.

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

“…Thus, anti-CTLA-4 may function best in the subset of patients with high levels of tumor-infiltrating lymphocytes (TILs) and intratumoral Tregs [22,26], low serum level of VEGF [27] and preexisting responses to tumor antigens such as NY-ESO-1 [20]. However, large prospective studies demonstrating the clinical utility of baseline markers that can predict CTLA-4 blockade effectiveness (as opposed to a pharmacokinetic/dynamic parameters) are still ongoing.…”

Serum Immunoregulatory Proteins as Predictors of Overall Survival of Metastatic Melanoma Patients Treated with Ipilimumab

“…10, 11), erythrocyte sedimentation rate (ESR; ref. 12), LDH (10)(11)(12)(13)(14), S100 protein (12), sCD25 (15), and VEGF (16)] were thought to associate with reduced benefit following ipilimumab treatment. In contrast, increased baseline ALC were associated with improved OS upon ipilimumab treatment (10)(11)(12)(13)(14)17).…”

Biomarkers of Response to Immune Modulatory Therapies in Cancer

“…The prognostic and/or predictive value of serum VEGF in relation to immune modulatory therapy had, however, remained undetermined. Yuan and colleagues retrospectively analysed serum VEGF levels in 176 patients with advanced melanoma, before and after therapy with ipilimumab [58]. Baseline VEGF levels were associated with clinical response, patients with a baseline serum VEGF value greater than 43pg/mL, treated with either 3 or 10mg/kg of ipilimumab were less likely to derive clinical benefit.…”

“…Shift in intra-tumoural CD8/T reg ratio [34] Increase in circulating ICOS + CD4 + effector T cells [41] Increase in Granzyme B + CD8 + T cells [42] Rise in absolute lymphocyte count [48,49] Baseline FoxP3 and IDO expression [44] Baseline 'immune active' tumour microenvironment [66] CTLA-4 + CD4 + effector T cells [49] EOMES + CD8 + T cells [50] Baseline circulating monocytic MDSCs [51] Reduction in monocytic MDSCs in periphery and tumour [52] Baseline serum VEGF [58] Baseline serum LDH [53] Maintenance of high frequency T cell clones in periphery [68] Neo-antigenic repertoire [71] …”