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.

Purpose: Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with a unique epitope specificity and Fc receptor binding profile optimized for activation of CD40-expressing antigen-presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1. Patients and Methods: We conducted a multicenter, open-label, phase II trial to evaluate the combination of sotigalimab 0.3 mg/kg and nivolumab 360 mg every 3 weeks in patients with advanced melanoma following confirmed disease progression on a PD-1 inhibitor. The primary objective was to determine the objective response rate (ORR). Results: Thirty-eight subjects were enrolled and evaluable for safety. Thirty-three were evaluable for activity. Five confirmed partial responses (PR) were observed for an ORR of 15%. Two PRs are ongoing at 45.9+ and 26+ months, whereas the other three responders relapsed at 41.1, 18.7, and 18.4 months. The median duration of response was at least 26 months. Two additional patients had stable disease for >6 months. Thirty-four patients (89%) experienced at least one adverse event (AE), and 13% experienced a grade 3 AE related to sotigalimab. The most common AEs were pyrexia, chills, nausea, fatigue, pruritus, elevated liver function, rash, vomiting, headache, arthralgia, asthenia, myalgia, and diarrhea. There were no treatment-related SAEs, deaths, or discontinuation of sotigalimab due to AEs. Conclusions: Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting. See related commentary by Wu and Luke, p. 9

Background Programmed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab. Methods In this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety. Results Objective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported. Conclusions Cosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile. Trial registration number NCT03212404.

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.

Gut microbiome (GM) and its either pro-tumorigenic or anti-tumorigenic role is intriguing and constitutes an evolving landscape in translational oncology. It has been suggested that these microorganisms may be involved in carcinogenesis, cancer treatment response and resistance, as well as predisposition to adverse effects. In melanoma patients, one of the most immunogenic cancers, immune checkpoint inhibitors (ICI) and MAPK-targeted therapy—BRAF/MEK inhibitors—have revolutionized prognosis, and the study of the microbiome as a modulating factor is thus appealing. Although BRAF/MEK inhibitors constitute one of the main backbones of treatment in melanoma, little is known about their impact on GM and how this might correlate with immune re-induction. On the contrary, ICI and their relationship to GM has become an interesting field of research due to the already-known impact of immunotherapy in modulating the immune system. Immune reprogramming in the tumor microenvironment has been established as one of the main targets of microbiome, since it can induce immunosuppressive phenotypes, promote inflammatory responses or conduct anti-tumor responses. As a result, ongoing clinical trials are evaluating the role of fecal microbiota transplant (FMT), as well as the impact of using dietary supplements, antibiotics and probiotics in the prediction of response to therapy. In this review, we provide an overview of GM’s link to cancer, its relationship with the immune system and how this may impact response to treatments in melanoma patients. We also discuss insights about novel therapeutic approaches including FMT, changes in diet and use of probiotics, prebiotics and symbiotics. Finally, we hypothesize on the possible pathways through which GM may impact anti-tumor efficacy in melanoma patients treated with targeted therapy, an appealing subject of which little is known.