The past year in melanoma research was marked by renewed optimism as new therapies advanced and regulatory scrutiny shaped development pathways. Lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy, emerged as a notable benchmark, while regulatory decisions and early microbiome-directed approaches added both momentum and caution to the field.
Lifileucel demonstrated durable responses in heavily pretreated unresectable or metastatic melanoma. Results from the phase 2 C-144-01 trial reported an objective response rate of 31.4% and a five-year overall survival rate of 19.7%. Median duration of response was 36.5 months, with many responses deepening over time. Short-term toxicities related to the required lymphodepleting chemotherapy and infusion — including thrombocytopenia and febrile neutropenia — occurred mostly within the first two weeks after treatment.
Clinicians emphasized the importance of timely referral and logistical coordination for TIL therapy. Treatment requires surgical tumor procurement for cell manufacturing and typically a two- to three-week inpatient period for lymphodepleting chemotherapy and the TIL infusion with interleukin-2, managed by experienced teams to monitor and treat acute toxicities. Rapid disease progression in some patients can narrow the treatment window, underscoring the need for early identification and referral to authorized centers.
C-144-01 was the first global, multicenter study to provide broader access to one-time autologous TIL therapy for patients refractory to standard therapies such as PD-1 inhibitors and, where applicable, targeted agents. The trial’s efficacy outcomes helped support regulatory approval of lifileucel for unresectable or metastatic melanoma after prior PD-1 therapy.
Regulatory developments tempered enthusiasm for other novel agents. In July, the FDA issued a complete response letter for Replimune’s biologics license application for RP1 (vusolimogene oderparepvec) in combination with nivolumab. The agency concluded that the pivotal IGNYTE trial did not meet the standards of an adequate and well-controlled study to establish effectiveness, citing heterogeneity in the patient population and concerns about the confirmatory trial design; no safety issues were identified. A subsequent Type A meeting did not yield a defined path forward.
Early clinical work on microbiome-targeted approaches showed encouraging signals. A phase 1 trial presented at ESMO 2025 found that the prebiotic camu camu, which contains the active compound castalagin, was safe when combined with immune checkpoint inhibitors in patients with melanoma and non–small cell lung cancer. The trial reported an objective response rate of 57% in a first-line melanoma cohort and 13% in refractory melanoma patients, suggesting potential enhancement of checkpoint inhibitor activity via gut microbiome modulation. Further mechanistic studies and trials with the purified compound castalagin are planned.
Collectively, these developments highlighted the evolving melanoma treatment landscape: durable benefit from next-generation cell therapies, the need for careful logistical and clinical pathways to deliver complex treatments, continued regulatory rigor, and growing interest in microbiome-based adjuncts to immunotherapy.
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