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Resistance to Immune Checkpoint Blockade (ICB) constitutes the current limiting factor for the optimal implementation of this novel therapy, which otherwise demonstrates durable responses with acceptable toxicity scores. This limitation is exacerbated by a lack of robust biomarkers. In this study, we have dissected the basal TME composition at the gene expression and cellular levels that predict response to Nivolumab and prognosis. BCR, TCR and HLA profiling were employed for further characterization of the molecular variables associated with response. The findings were validated using a single-cell RNA-seq data of metastatic melanoma patients treated with ICB, and by multispectral immunofluorescence. Finally, machine learning was employed to construct a prediction algorithm that was validated across eight metastatic melanoma cohorts treated with ICB. Using this strategy, we have unmasked a major role played by basal intratumoral Plasma cells expressing high levels of IGKC in efficacy. IGKC, differentially expressed in good responders, was also identified within the Top response-related BCR clonotypes, together with IGK variants. These results were validated at gene, cellular and protein levels; CD138+ Plasma-like and Plasma cells were more abundant in good responders and correlated with the same RNA-seq-defined fraction. Finally, we generated a 15-gene prediction model that outperformed the current reference score in eight ICB-treated metastatic melanoma cohorts. The evidenced major contribution of basal intratumoral IGKC and Plasma cells in good response and outcome in ICB in metastatic melanoma is a groundbreaking finding in the field beyond the role of T lymphocytes.

[Purpose]: Intestinal dysbiosis has emerged as a biomarker of response to immune checkpoint inhibitors (ICIs). It can be caused by antibiotics, although it may also result from the use of other drugs that have been studied to a lesser extent. The objective of our study was to analyze the association between the use of potentially dysbiosis-related drugs and survival in patients treated with ICIs in the clinical practice., [Materials and methods]: A retrospective, multicenter, cohort study was conducted. Clinicopathological variables were collected and the concomitant use of drugs was analyzed. A descriptive analysis of variables and overall survival, estimated by the Kaplan–Meier method, was performed, and association with various independent variables was assessed using Cox regression., [Results]: We included 253 patients, mainly with non-small cell lung cancer and melanoma. The most commonly used drugs were acid reducers, prescribed to 55.3% of patients, followed by corticosteroids (37.9%), anxiolytic drugs (35.6%), and antibiotics (20.5%). The use of acid reducers (9 vs. 18 months, P, [Conclusion]: Response to ICIs may be influenced by the use of drugs that lead to intestinal dysbiosis. Although a confirmatory prospective controlled study is required, our findings should be taken into account when analyzing ICI efficacy.

Background: The analysis of gene expression levels is used in many clinical studies to know how patients evolve or to find new genetic biomarkers that could help in clinical decision making. However, the techniques and software available for these analyses are not intended for physicians, but for geneticists. However, enabling physicians to make initial discoveries on these data would benefit in the clinical assay development. Results: Melanoma is a highly immunogenic tumor. Therefore, in recent years physicians have incorporated immune system altering drugs into their therapeutic arsenal against this disease, revolutionizing the treatment of patients with an advanced stage of the cancer. This has led us to explore and deepen our knowledge of the immunology surrounding melanoma, in order to optimize the approach. Within this project we have developed a database for collecting relevant clinical information for melanoma patients, including the storage of patient gene expression levels obtained from the NanoString platform (several samples are taken from each patient). The Immune Profiling Panel is used in this case. This database is being exploited through the analysis of the different expression profiles of the patients. This analysis is being done with Python, and a parallel version of the algorithms is available with Apache Spark to provide scalability as needed. Conclusions: VIGLA-M, the visual analysis tool for gene expression levels in melanoma patients is available at http://khaos.uma.es/melanoma/. The platform with real clinical data can be accessed with a demo user account, physician, using password physician_test_7634 (if you encounter any problems, contact us at this email address: mailto: khaos@lcc.uma.es). The initial results of the analysis of gene expression levels using these tools are providing first insights into the patients’ evolution. These results are promising, but larger scale tests must be developed once new patients have been sequenced, to discover new genetic biomarkers. Ministerio de Educación y Ciencia TIN2017-86049-R Ministerio de Educación y Ciencia TIN2014-58304-R Junta de Andalucía P12-TIC-1519

The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain., Novartis have provided funding for this observational study.