Francisco Aya

Background: Immune checkpoint inhibitors (ICIs) targeting PD-1 have significantly improved outcomes in patients with advanced melanoma. However, the optimal treatment duration remains undefined. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for treatment response monitoring and surveillance and can predict long-term clinical outcomes. Methods: Clinical and ctDNA data from prospectively enrolled patients with stage IV melanoma treated with anti–PD-1-based therapy at a single academic center were retrospectively analyzed. Of the 56 patients eligible, 28 underwent serial ctDNA testing during ICI treatment and follow-up (median 31 months) using a personalized, tumor-informed assay. Landmark analysis at 6 and 9 months was performed to assess progression-free survival (PFS) based on ctDNA status. Multivariable Cox regression was used to identify independent predictors of long-term outcomes. Results: Pre-ICI treatment, 91.7% (11/12) of evaluable patients were ctDNA-positive. At 6 months, ctDNA negativity or clearance was observed in 47.4% (9/19), and was strongly associated with improved PFS in the landmark analysis (HR: 10.0, p = 0.03; 2-year PFS: 89% in ctDNA-negative versus 30% in ctDNA-positive groups). At 9 months, persistent ctDNA positivity trended toward worse PFS. Multivariate analysis confirmed ctDNA status at the 6-month landmark timepoint to be an independent predictor of long-term benefit. Conclusions: Tumor-informed ctDNA testing is a robust, non-invasive tool to predict long-term benefit from anti–PD-1-based therapy in advanced melanoma. ctDNA clearance or sustained negativity at 6 months may serve as a surrogate for durable response and could inform individualized treatment discontinuation strategies, and minimize toxicity and cost while maintaining efficacy. These findings, derived from a limited single-center cohort, warrant further exploration and validation in larger studies.

Immunotherapy, particularly immune checkpoint inhibitors, plays a crucial role in the treatment of brain metastases in various primary cancers. Response assessment encompasses atypical patterns, including pseudoprogression, hyperprogression, or dissociated response, which present greater complexity than classical patterns defined by standardized response assessment criteria. Additionally, intracranial adverse events like hypophysitis or encephalitis may resemble tumor progression. Accurate evaluation and management of brain metastases during immunotherapy requires that radiologists are familiar with both classical and atypical response patterns, as well as potential intracranial adverse events. Brain MRI and advanced imaging techniques serve as essential tools for this purpose. Critical relevance statement: Assessing brain metastases response to immunotherapy accurately is fundamental for therapeutic decision-making. Radiologists must recognize classical and atypical responses and adverse events associated with immunotherapy to ensure optimal patient management. Key Points: Immunotherapy response assessment in brain metastases is complex due to atypical patterns including pseudoprogression, hyperprogression, and dissociated responses. Immunotherapy-induced intracranial adverse events, such as hypophysitis and encephalitis, must be accurately identified. Brain MRI, complemented by advanced imaging techniques (perfusion MRI, MRS, and amino acid PET), is crucial for distinguishing these complex scenarios. Graphical

The Spanish Group for Cancer Immuno-Biotherapies (GÉTICA) held the XI Forum on Translational Immunology and Cancer Immunotherapy (FIT Cancer 11) from 13 to 15 March 2025, in Madrid (Spain). FITCancer is the largest meeting uniquely focused on cancer immunotherapy in Spain and brings together clinicians and researchers with expertise in the field of cancer immunology and immunotherapy. Here, we present abstracts submitted by GÉTICA’s members to the XI Forum on Translational Immunology and Cancer Immunotherapy, which were divided into the following three topics: novel therapeutic targets and strategies, cell-based immunotherapies, and clinical scenarios and potential biomarkers.

The Spanish Group for Cancer Immuno-Biotherapies (GÉTICA) held the X Forum on Translational Immunology and Cancer Immunotherapy (FIT Cancer 10) from 14 to 16 March 2024, in Seville (Spain). FIT Cancer is the largest meeting uniquely focused on cancer immunotherapy in Spain and brings together clinicians and researchers, with expertise in the field of cancer immunology and immunotherapy. Here, we present abstracts submitted by GÉTICA’s members to the X Forum on Translational Immunology and Cancer Immunotherapy, which were divided into three topics: cell-based immunotherapies, novel therapeutic targets and strategies and clinical scenarios and potential biomarkers.

The treatment landscape for advanced melanoma has transformed significantly with the advent of BRAF and MEK inhibitors (BRAF/MEKi) targeting BRAFV600 mutations, as well as immune checkpoint inhibitors (ICI) like anti-PD-1 monotherapy or its combinations with anti-CTLA-4 or anti-LAG-3. Despite that, many patients still do not benefit from these treatments at all or develop resistance mechanisms. Therefore, prognostic and predictive biomarkers are needed to identify patients who should switch or escalate their treatment strategies or initiate an intensive follow-up. In melanoma, liquid biopsy has shown promising results, with a potential role in predicting relapse in resected high-risk patients or in disease monitoring during the treatment of advanced disease. Several components in peripheral blood have been analyzed, such as circulating tumor cells (CTCs), cell-free DNA (cfDNA), and circulant tumoral DNA (ctDNA), which have turned out to be particularly promising. To analyze ctDNA in blood, different techniques have proven to be useful, including digital droplet polymerase chain reaction (ddPCR) to detect specific mutations and, more recently, next-generation sequencing (NGS) techniques, which allow analyzing a broader repertoire of the mutation landscape of each patient. In this review, our goal is to update the current understanding of liquid biopsy, focusing on the use of ctDNA as a biological material in the daily clinical management of melanoma patients, in particular those with advanced disease treated with ICI.

Melanoma is the most aggressive and deadly form of skin cancer, and its incidence has been steadily increasing over the past few decades, particularly in the Caucasian population. Immune checkpoint inhibitors (ICI), anti-PD-1 monotherapy or in combination with anti-CTLA-4, and more recently, anti-PD-1 plus anti-LAG-3 have changed the clinical evolution of this disease. However, a significant percentage of patients do not benefit from these therapies. Therefore, to improve patient selection, it is imperative to look for novel biomarkers. Immune subsets, particularly the quantification of lymphocyte T populations, could contribute to the identification of ICI responders. The main purpose of this review is to thoroughly examine significant published data on the potential role of lymphocyte T subset distribution in peripheral blood (PB) or intratumorally as prognostic and predictive of response biomarkers in advanced melanoma patients treated with ICI regardless of BRAFV600 mutational status.

Melanoma is the most aggressive and deadly form of skin cancer, and its incidence has been steadily increasing over the past few decades, particularly in the Caucasian population [1]. Current treatment strategies, the combination of BRAF and MEK inhibitors (BRAF/MEKi) in BRAFV600 mutant melanoma, and immune checkpoint inhibitors (ICI), have changed the clinical evolution of this disease [2]. However, a significant percentage of patients do not benefit from these therapies. Therefore, to improve patient selection, it is imperative to look for novel biomarkers. Immune subsets, particularly the quantification of lymphoid populations, could contribute to the identification of ICI responders. The aim of this review is to thoroughly examine significant published data on this topic in melanoma patients and to evaluate the potential role of lymphoid subsets as prognostic and predictive response biomarkers.

Background: Melanoma is the cancer with the highest risk of dissemination to the central nervous system (CNS), one of the leading causes of mortality from this cancer. Objective: To identify patients at higher risk of developing CNS metastases and to evaluate associated prognostic factors. Methods: A cohort study (1998–2023) assessed patients who developed CNS melanoma metastases. Multivariate logistic regression was used to identify predictive factors at melanoma diagnosis for CNS metastasis. Cox regression analysis evaluated the CNS-independent metastasis-related variables impacting survival. Results: Out of 4718 patients, 380 (8.05%) developed CNS metastases. Multivariate logistic regression showed that a higher Breslow index, mitotic rate ≥ 1 mm², ulceration, and microscopic satellitosis were significant risk factors for CNS metastasis development. Higher patient age and the location of the primary tumor in the upper or lower extremities were protective factors. In survival analysis, post-CNS metastasis, symptomatic disease, prior non-CNS metastases, CNS debut with multiple metastases, elevated LDH levels, and leptomeningeal involvement correlated with poorer survival. Conclusion: Predictive factors in the primary tumor independently associated with brain metastases include microscopic satellitosis, ulceration, higher Breslow index, and trunk location. Prognostic factors for lower survival in CNS disease include symptomatic disease, multiple CNS metastases, and previous metastases from different sites.

Immune-related adverse events (irAEs) are frequent and could be associated with improved response to immune checkpoint inhibitors (ICIs). A prospective cohort of advanced melanoma patients receiving ICI as first-line therapy was retrospectively reviewed (January 2011–February 2019). A total of 116 of 153 patients presented with at least one irAE (75.8%). The most frequent irAEs were dermatological (derm irAEs, 50%), asthenia (38%), and gastrointestinal (29%). Most irAEs appeared within the first 90 days, while 11.2% appeared after discontinuation of the therapy. Mild grade 1–2 derm irAEs tended to appear within the first 2 months of therapy with a median time of 65.5 days (IQR 26-139.25), while grade 3–4 derm irAEs appeared later (median 114 days; IQR 69-218) and could be detected at any time during therapy. Only derm irAE occurrence was related to improved survival (HR 6.46). Patients presenting derm irAEs showed better 5-year overall survival compared to those with no derm irAEs (53.1% versus 24.9%; p < 0.001). However, the difference was not significant when adjusting for the duration of therapy. In conclusion: the timeline of immune-related-AEs differs according to the organ involved. The (apparent) improved survival of patients who present derm AEs during immunotherapy could be partially explained by longer times under treatment.