Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.
Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations. Previous preclinical studies suggested that an intermittent dosing of these drugs could delay the emergence of resistance. Contrary to expectations, the first published phase 2 randomized study comparing continuous versus intermittent schedule of dabrafenib (BRAFi) plus trametinib (MEKi) demonstrated a detrimental effect of the “on−off” schedule. Here we report confirmatory data from the Phase II randomized open-label clinical trial comparing the antitumoral activity of the standard schedule versus an intermittent combination of vemurafenib (BRAFi) plus cobimetinib (MEKi) in advanced BRAF mutant melanoma patients (NCT02583516). The trial did not meet its primary endpoint of progression free survival (PFS) improvement. Our results show that the antitumor activity of the experimental intermittent schedule of vemurafenib plus cobimetinib is not superior to the standard continuous schedule. Detection of BRAF mutation in cell free tumor DNA has prognostic value for survival and its dynamics has an excellent correlation with clinical response, but not with progression. NGS analysis demonstrated de novo mutations in resistant cases.
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.
Malignant melanoma is one of the most common causes of cancer and cancer deaths in young people. Until few years ago, scarce drugs have proven efficacy in metastatic setting. However, in the recent years, the treatment of metastatic malignant melanoma has undergone the incorporation of effective treatment such as immunotherapy, the use of tyrosine kinase inhibitors and the emergence of other cytostatic compounds, like the nanoparticles. This review aims to propose a standardization to classify the different types of nanoparticles, according to chemical aspects, and update the clinical research with nanoparticles and their use in melanoma field.
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.
BackgroundA significant number of melanoma patients treated with anti-PD-1 alone or in combination with anti-CTLA-4 have transient or no response to treatment. Sotigalimab is a CD40 agonist antibody with unique epitope specificity and Fc receptor binding profile for optimal therapeutic application. Preclinical studies suggest that sotigalimab can be combined with PD-1 blockade to trigger effective anti-tumor immunity. We conducted a multi-center, open label, Phase Ib-parallel arm phase II trial (NCT03123783) to evaluate the combination of sotigalimab with nivolumab in subjects with anti-PD-1/PD-L1 refractory metastatic melanoma.MethodsThe study objective was to evaluate the efficacy and safety of sotigalimab in combination with nivolumab in anti-PD-1/PD-L1 refractory advanced melanoma patients. Subjects received sotigalimab (0.3mg/kg) combined with nivolumab (360mg) every 3 weeks. Thirty-eight subjects with unresectable or metastatic melanoma who had confirmed progressive disease during treatment with anti-PD-1 therapy (documented by 2 consecutive tumor assessments) were enrolled (evaluable for safety) and 33 subjects were evaluable for efficacy.ResultsSix subjects had PR (including one unconfirmed PR) for an ORR of 18%. The mDOR was 18.7 months. Two subjects with PR received treatment for >2 years. Three of the six responding subjects remain off all therapy for ≥26 months, and one patient required stereotactic radiosurgery to a single brain lesion ten months after stopping therapy and has not required additional local or systemic therapy since. Three additional subjects had prolonged SD (12.6, 7.6, 6.2 months). The DCR was 48% and 33% of subjects experienced reduction in target lesions. Efficacy was observed in patients regardless of their tumor PD-L1 expression. The overall safety profile of the combination is consistent with the profiles of individual agents. The majority of AEs observed were of mild to moderate intensity (CTCAE Grade ≤2). The most commonly observed AEs were: pyrexia, chills, nausea, fatigue, pruritus, transaminitis, headache, asthenia, myalgia, rash, vomiting and arthralgia. There were no Grade 4 or 5 AEs related to study drugs. There were no treatment discontinuations due to AEs.ConclusionsThe combination of sotigalimab and nivolumab demonstrated treatment benefit (tumor response or prolonged disease control) in anti-PD-1/PD-L1 refractory melanoma patients with an overall favorable safety and tolerability profile. Notably, a subset of patients remain in response off treatment for ≥26 months. These results warrant further study of this combination in advanced, refractory melanoma.AcknowledgementsWe extend our gratitude to the patients and their families who made this trial possible and the clinical study teams involved in this trial. We thank BMS for providing the nivolumab for this study.Trial RegistrationNCT03123783Ethics ApprovalThis study was approved by the Institutional Review Boards at Yale University (#20170300), University of Nebraska Medical Center (#543-18-CB) and The Hospital Regional de Málaga (#19.03.1341E1-GHM).
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