ONCOLYTIC immunotherapy with nivolumab yields durable responses in patients with anti-PD-1 failed advanced cutaneous melanoma cases. Although cellular therapy lifileucel received FDA approval as a treatment following anti-PD-1 progression, severe treatment-emergent adverse events and complex administration highlight an urgent clinical need for less toxic, highly effective modalities. To address this gap, investigators evaluated RP1, an engineered herpes simplex virus type 1 based oncolytic agent expressing GM-CSF and a fusogenic protein, combined with anti-PD-1 blockade in the registrational phase II cohort of the IGNYTE trial.
Among 140 enrolled patients who experienced disease progression during prior anti-PD-1 therapy, the combination achieved a confirmed objective response rate of 32.9% by RECIST 1.1, including a 15.0% complete response rate. Responses were observed regardless of baseline disease burden, BRAF mutation status, or whether patients had received prior anti-CTLA-4 therapy. Notably, tumor regression occurred with similar depth and durability across both injected lesions and non-injected sites, including visceral metastases in the lungs and liver.
Biomarker analysis revealed that oncolytic immunotherapy induced broad intra-tumoral immune activation, converting immunologically cold lesions into highly active environments. Biopsies taken on treatment demonstrated marked increases in CD8 positive T cell infiltration and elevated PD-L1 expression compared to baseline. RNA sequencing further identified 313 significantly upregulated differentially expressed genes involved in T cell, B cell, and natural killer cell pathways among responding patients, establishing an antiviral immune signature associated with systemic control.
The median duration of response reached 33.7 months, with nearly 70% of responses ongoing at one year. Overall survival rates at one and two years were 75.3% and 63.3%, respectively, while median overall survival was not reached for responders. Crucially, the regimen demonstrated a favorable safety profile. Most treatment-related adverse events were transient grade 1 or 2 flu-like symptoms, including fatigue, chills, and pyrexia. Grade 3 or 4 treatment-related adverse events occurred in only 12.9% of patients, and no treatment-related deaths were reported, positioning this combination as a manageable therapeutic approach.
Reference
Wong MK et al. RP1 Combined With Nivolumab in Advanced Anti-PD-1-Failed Melanoma (IGNYTE). J Clin Oncol. 2025;43(33):3589-3599.
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