Abstract
Patients with locally/regionally advanced melanoma were treated with neoadjuvant combination immunotherapy with high-dose interferon α-2b (HDI) and ipilimumab in a phase I clinical trial. Tumor specimens were obtained prior to the initiation of neoadjuvant therapy, at the time of surgery and progression if available. In this study, gene expression profiles of tumor specimens (N = 27) were investigated using the NanoString nCounter® platform to evaluate associations with clinical outcomes (pathologic response, radiologic response, relapse-free survival (RFS), and overall survival (OS)) and define biomarkers associated with tumor response. The Tumor Inflammation Signature (TIS), an 18-gene signature that enriches for response to Programmed cell death protein 1 (PD-1) checkpoint blockade, was also evaluated for association with clinical response and survival. It was observed that neoadjuvant ipilimumab-HDI therapy demonstrated an upregulation of immune-related genes, chemokines, and transcription regulator genes involved in immune cell activation, function, or cell proliferation. Importantly, increased expression of baseline pro-inflammatory genes CCL19, CD3D, CD8A, CD22, LY9, IL12RB1, C1S, C7, AMICA1, TIAM1, TIGIT, THY1 was associated with longer OS (p < 0.05). In addition, multiple genes that encode a component or a regulator of the extracellular matrix such as MMP2 and COL1A2 were identified post-treatment as being associated with longer RFS and OS. In all baseline tissues, high TIS scores were associated with longer OS (p = 0.0166). Also, downregulated expression of cell proliferation-related genes such as CUL1, CCND1 and AAMP at baseline was associated with pathological and radiological response (unadjusted p < 0.01). In conclusion, we identified numerous genes that play roles in multiple biological pathways involved in immune activation, immune suppression and cell proliferation correlating with pathological/radiological responses following neoadjuvant immunotherapy highlighting the complexity of immune responses modulated by immunotherapy. Our observations suggest that TIS may be a useful biomarker for predicting survival outcomes with combination immunotherapy.
Highlights
Stage III melanoma encompasses regional lymphatic and/or lymph node involvement, for which the current standard of care is surgery followed by adjuvant therapy
In the phase III E1609 trial, ipilimumab was compared with high dose interferon α-2b (HDI) as adjuvant therapy in high risk stage III/IV melanoma patients, and ipilimumab at the 3 mg/kg dose was associated with improved overall survival when compared to HDI treatment [11,12,13]
Based on modified World Health Organization (mWHO) criteria, radiological response was observed in 10 patients (37%,) while 10 showed stable disease and 7 patients showed radiologic progression of disease
Summary
Stage III melanoma encompasses regional lymphatic and/or lymph node involvement, for which the current standard of care is surgery followed by adjuvant therapy. Adjuvant therapy with immune checkpoint blockade has demonstrated significant relapse-free survival (RFS) benefits, leading to US Food and Drug Administration (FDA) approval of single-agent ipilimumab (CTLA-4 blockade), nivolumab (PD-1 blockade) and pembrolizumab (PD-1 blockade) for adjuvant treatment of patients with high-risk stage III melanoma following complete resection [3,4,5,6,7,8,9,10]. In the phase III E1609 trial, ipilimumab was compared with HDI as adjuvant therapy in high risk stage III/IV melanoma patients, and ipilimumab at the 3 mg/kg dose was associated with improved overall survival when compared to HDI treatment [11,12,13]. A gene-set scoring study has indicated that natural killer (NK) cell infiltration is associated with an improved survival rate in metastatic cutaneous melanoma [26]
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