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Abstract Background Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections. Methods This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age Results Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3–4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission. Conclusion Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.

Introduction: Advances in modern therapies have improved outcomes for patients with melanoma brain metastases (MBM), though prognosis remains poor. The optimal treatment strategy for patients who do not meet clinical trial inclusion criteria is unclear., Methods: This study included all patients with MBM diagnosed in Denmark between 2015 and 2022, identified through the Danish Metastatic Melanoma Database (DAMMED) and local surgical and radiotherapy records. Data were collected from electronic patient records., Results: A total of 838 patients were included, with a median overall survival (OS) of 9.0 months. Of these, 112 (19.4 %) survived beyond 3 years post-diagnosis. Patients treated with immune checkpoint inhibitors (ICI) as first line treatment, specifically ipilimumab + nivolumab, demonstrated an intracranial overall response rate (icORR) of 46 % and a 2-year OS of 49 %. Those treated with BRAF/MEK inhibitors (BRAF/MEKi) had an icORR of 56 % but a 2-year OS of 20 %. Patients with leptomeningeal disease (LMD, n = 67) had a median OS of 8.4 months. Systemic therapy was associated with a superior OS for patients with LMD, though no survival benefit was seen with ICI compared to BRAF/MEKi. Among the 230 patients who underwent surgery, 30 received postoperative stereotactic radiosurgery (SRS); however, there was no difference in OS or intracranial progression-free survival between the groups., Conclusion: A considerable proportion of patients with brain metastases diagnosed after 2015 survived more than 3 years. Patients with LMD appeared to obtain limited benefit of ICI with only few patients alive > 3 years post-diagnosis., Competing Interests: Declaration of Competing Interest Within the last two years, CAH received honoraries for lectures from GSK and Bristol Myers Squibb. MD has received proprietary data access from Bristol Myers Squibb and Genentech and is advisor of Achilles Therapeutics. HS received honoraries for consultancies and lectures from Novartis, Merck, Bristol-Myers Squibb, and Incyte; and restricted research grants from MSD. LB served on the advisory board of Bristol-Myers Squibb, Roche, Novartis, Merck, EISAI, and Bayer Healthcare. IMS has received honoraria for consultancies and lectures from Novartis, Roche, Merck, and Bristol Myers Squibb; a restricted research grant from Novartis; and financial support for attending symposia from Bristol Myers Squibb, Merck, Novartis, Pfizer, and Roche. EE received honoraries for consultancies and lectures from Novartis, Merck, Bristol-Myers Squibb, and Pierre Fabre, and conference and travel coverage from Pierre Fabre and Merck. All remaining authors have declared no conflicts of interest., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Groundbreaking studies have reshaped the treatment landscape for patients with resectable stage ≥IIIB melanoma by demonstrating the benefits of neoadjuvant therapy. Data from the NADINA and SWOG S1801 trials reveal substantial improvements in event-free survival compared to adjuvant therapy alone. These studies employed distinct neoadjuvant immunotherapy approaches - ipilimumab plus nivolumab in NADINA and anti-PD-1 monotherapy in SWOG S1801 - highlighting potential differences in efficacy and toxicity. The integration of biomarkers may improve the risk/benefit ratio by enabling personalized treatment selection between ipilimumab plus nivolumab versus anti-PD-1 monotherapy. In metastatic melanoma, molecular biomarkers such as BRAF mutational status and intratumoral PD-L1 expression can help guide treatment decisions; however, their, and other biomarkers', role in the neoadjuvant context has yet to be fully investigated. This commentary underscores the need to investigate whether these molecular markers, along with other biomarkers and clinical parameters, can inform neoadjuvant therapy in resectable stage ≥IIIB melanoma. We propose a coordinated effort involving retrospective analyses of current trials and prospective clinical studies, to define the role of biomarkers. A biomarker-guided approach could optimize efficacy and reduce toxicity, offering personalized treatment options for patients with resectable melanoma. As implementation of neoadjuvant therapy rapidly gains global adoption, we advocate for robust research to ensure that each patient receives the most effective and least toxic therapeutic option., Competing Interests: Declaration of Competing Interest EE received honoraria for consultancies and lectures from Novartis, Merck, Bristol-Myers Squibb, and Pierre Fabre, and conference and travel coverage from Pierre Fabre and Merck. MD is advisor of Achilles Therapeutics and member of expert network of Guidepoint LLC and Alphasights. IMS has received honoraria for consultancies and lectures from Novartis, Roche, Merck, and Bristol Myers Squibb; a restricted research grant from Novartis; and financial support for attending symposia from Bristol Myers Squibb, Merck, Novartis, Pfizer, and Roche., (Copyright © 2025. Published by Elsevier Ltd.)

Background: Therapeutic advances have reshaped the treatment landscape for patients with resectable melanoma, particularly for those with stage IIB/C and stage III disease. In this article, we discuss the current status and future outlook of adjuvant immunotherapy for melanoma in Europe., Results: Adjuvant immunotherapy offers significant benefits in terms of recurrence-free survival and distant metastasis-free survival. Uncertainties regarding overall survival (OS) benefits, however, remain. Trials such as Keynote-054, which are expected to provide crucial OS information, have delayed their final analyses until 2027. Additionally, real-world studies have raised questions about the correlation between recurrence-free survival/distant metastasis-free survival improvements observed in clinical trials and OS outcomes in routine clinical practice. These uncertainties have led to ongoing debates about the cost-effectiveness of adjuvant therapies, with disparities in reimbursement policies across Europe reflecting these concerns., Conclusion: Looking ahead to 2028, adjuvant immunotherapy will remain a key option of comprehensive melanoma care, particularly for patients with stage IIB/C and stage III with micrometastatic disease, where neoadjuvant immunotherapy is not feasible., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has proved to be an effective treatment for metastatic melanoma, even in patients failing anti-PD-1 blockade. Nevertheless, progression is observed in a substantial subgroup of patients following an initial objective response to treatment with TILs. These patients might benefit from additional consolidating treatment before clinical progression, but thus far, it is not possible to identify this subgroup of patients prone to progress. In this study the predictive value of early metabolic response after TIL therapy is explored. Materials and methods: 60 patients treated with TIL therapy in 4 different clinical trials and with available [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography-CT (FDG-PET/CT) scans at baseline and at least one follow-up scan 6-8 weeks and/or 12-16 weeks post-TIL infusion were included. Results: Obtaining complete metabolic response (CMR) was associated with significantly superior median overall survival (mOS) compared with not obtaining CMR (p<0.0001). Of particular interest, metabolic response divided RECIST partial responders (22 patients) into two groups with significantly different clinical outcomes. Neither mOS (range 32.2-149.8+) nor median progression-free survival (mPFS; range 20.7-123.4+) were reached for patients with partial response (PR)/CMR (10 patients), whereas patients with PR/non-CMR (12 patients) had a mOS of 28.7 months (p=0.0016) and a mPFS of 7.8 months (p<0.0001).Overall, not achieving a CMR was associated with a short mPFS of 3.2 months, and 97.9% (47/48) of all patients in this group progressed within 12 months. Conclusion: In conclusion, early CMR is a strong predictor of long-term survival after TIL therapy in metastatic melanoma patients. Furthermore, FDG-PET/CT scans appear superior to CT scans for providing early prognostic information after TIL therapy in melanoma and can be used to tailor patient-specific management and follow-up strategies., Competing Interests: Competing interests: THB has received speaker’s fee from Bristol-Myers Squibb (BMS). EE has received speaker’s fee from BMS, Merck Sharpe and Dohme (MSD), Pierre Fabre, Novartis and Pfizer, and travel support from MSD and Pierre Fabre. IMS has an advisory board relationship with Instil Bio, Mendus, and Novartis; has received speaker’s fee from BMS, MSD, Sanofi, Takeda; has stocks in IO Biotech; and has received institutional grants for research from Adaptimmune, Asgard Therapeutics, Evaxion, IO Biotech, Lytix Biopharma and TILT Biotherapeutics. RA, HH and KM reports no conflicts of interest., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)