A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

Abstract

BackgroundIpilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.MethodsIn this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.ResultsObjective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.ConclusionsBaseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.

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

“…The ratio of tumor-infiltrating CD8 + T effector cells to FoxP3 + Tregs after ipilimumab infusion was tightly correlated with the extent of tumor shrinkage in MM and ovarian cancer patients [18,21]. This correlation between a high CD8 + T effector/Treg ratio and tumor regression has been observed in patients treated with the human IgG1 ipilimumab (which mediates ADCC) but less frequently in those treated with the IgG2 tremelimumab [22,23]. CD4 + ICOS high IFNγ + T cells recognizing tumor epitopes were found after radical prostatectomy in prostate cancers and non-malignant tissues post-neoadjuvant ipilimumab [24].…”

“…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.…”

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

“…Many of the new immune therapies either require the presence of pre-existing T cells in the tumor, 12 , 26 , 27 or rely on sufficient tumor homing of tumor specific T cells after peripheral or in vitro activation. 14 , 28 …”

Microenvironnement immunitaire et cancer

“…Ainsi, dans les cancers du côlon, la [13,35]. Dans le même cadre, il a été observé que la surexpression de FOXP3 (forkhead box P3, un marqueur de lymphocytes T régulateurs) et de la protéine IDO est corrélée positivement avec l'efficacité de l'ipilimumab [36]. De même, les tumeurs exprimant les ligands PD-1 semblent être sensibles à la thérapie anti-PD-1 [16].…”