Case report: Therapeutic potential of T-VEC in combination with MEK inhibitors in melanoma patients with NRAS mutation.

Mutations in the NRAS gene are common alterations in malignant melanoma. However, there are no specific treatment options approved for NRAS-mutated melanoma patients besides immune checkpoint inhibition. Since preclinical data suggests a synergistic effect of a MEK inhibitor (MEKi) and the oncolytic virus talimogene laherparepvec (T-VEC), we have treated three melanoma patients with this combination. All of the three patients had been suffering from recurring cutaneous and subcutaneous in-transit metastases. Upon treatment one patient (case 1) presented full regression of locoregional metastases and remained progression-free until date, for almost three years. The second patient (case 2) showed a partial regression of painful gluteal satellite metastases but died from brain metastases. The third patient (case 3) showed a durable response of locoregional metastases for seven months. The combination treatment was well tolerated with common adverse events known for each single agent. This report is the first case series presenting a clinical benefit of the combined T-VEC and MEKi treatment. We suggest the combination of T-VEC and MEKi as an off-label treatment option for patients with NRAS mutations, especially with recurrent in-transit or satellite metastases.

Immunosuppressive capacity of circulating MDSC predicts response to immune checkpoint inhibitors in melanoma patients.

Purpose: Although the treatment of advanced melanoma patients with immune checkpoint inhibitors (ICI) significantly increased the therapeutic efficiency, many patients remain resistant to ICI that could be due to immunosuppression mediated by myeloid-derived suppressor cells (MDSC). These cells are enriched and activated in melanoma patients and could be considered as therapeutic targets. Here we studied dynamic changes in immunosuppressive pattern and activity of circulating MDSC from melanoma patients treated with ICI. Experimental design: MDSC frequency, immunosuppressive markers and function were evaluated in freshly isolated peripheral blood mononuclear cells (PBMC) from 29 melanoma patients receiving ICI. Blood samples were taken prior and during the treatment and analyzed by flow cytometry and bio-plex assay. Results: MDSC frequency was significantly increased before the therapy and through three months of treatment in non-responders as compared to responders. Prior to the ICI therapy, MDSC from non-responders displayed high levels of immunosuppression measured by the inhibition of T cell proliferation assay, whereas MDSC from responding patients failed to inhibit T cells. Patients without visible metastasis were characterized by the absence of MDSC immunosuppressive activity during the ICI treatment. Moreover, non-responders showed significantly higher IL-6 and IL-8 concentrations before therapy and after the first ICI application as compared to responders. Conclusions: Our findings highlight the role of MDSC during melanoma progression and suggest that frequency and immunosuppressive activity of circulating MDSC before and during the ICI treatment of melanoma patients could be used as biomarkers of response to ICI therapy.

Potential therapeutic effect of low-dose paclitaxel in melanoma patients resistant to immune checkpoint blockade: A pilot study.

The low dose application of chemotherapeutic agents such as paclitaxel was previously shown to initiate anti-tumor activity by neutralizing myeloid-derived suppressor cells (MDSCs) in melanoma mouse models. Here, we investigated immunomodulating effects of low-dose paclitaxel in 9 metastatic melanoma patients resistant to prior treatments. Three patients showed response to therapy (two partial responses and one stable disease). In responding patients, paclitaxel decreased the frequency and immunosuppressive pattern of MDSCs in the peripheral blood and skin metastases. Furthermore, paclitaxel modulated levels of inflammatory mediators in the serum. In addition, responders displayed enhanced frequencies of tumor-infiltrating CD8+ T cells and their activity indicated by the upregulation of CD25 and TCR ζ-chain expression. Our study suggests that low-dose paclitaxel treatment could improve clinical outcome of some advanced melanoma patients by enhancing anti-tumor immunity and might be proposed for combined melanoma immunotherapy.

Eosinophil accumulation predicts response to melanoma treatment with immune checkpoint inhibitors.

Eosinophils have been identified as a prognostic marker in immunotherapy of melanoma and suggested to contribute to anti-tumor host defense. However, the influence of immune checkpoint inhibitors (ICI) on the eosinophil population is poorly studied. Here, we applied routine laboratory tests, multicolor flow cytometry, RNA microarray analysis, and bio-plex assay to analyze circulating eosinophils and related serum inflammatory factors in 32 patients treated with pembrolizumab or the combination of nivolumab and ipilimumab. We demonstrated that clinical responses to ICI treatment were associated with an eosinophil accumulation in the peripheral blood. Moreover, immunotherapy led to the alteration of the eosinophil genetic and activation profile. Elevated serum concentrations of IL-16 during ICI treatment were found to be associated with increased frequencies of eosinophils in the peripheral blood. Using immunohistochemistry, we observed an enhanced eosinophil degranulation and a positive correlation between eosinophil and CD8+ T cell infiltration of tumor tissues from melanoma patients treated with ICI. Our findings highlight additional mechanisms of ICI effects and suggest the level of eosinophils as a novel predictive marker for melanoma patients who may benefit from this immunotherapy.

Opposing roles of eosinophils in cancer.

Eosinophils are a subset of granulocytes mostly known for their ability to combat parasites and induce allergy. Although they were described to be related to cancer more than 100 years ago, their role in tumors is still undefined. Recent observations revealed that they display regulatory functions towards other immune cell subsets in the tumor microenvironment or direct cytotoxic functions against tumor cells, leading to either antitumor or protumor effects. This paradoxical role of eosinophils was suggested to be dependent on the different factors in the TME. In addition, the clinical relevance of these cells has been recently addressed. In most cases, the accumulation of eosinophils both in the tumor tissue, called tumor-associated tissue eosinophilia, and in the peripheral blood were reported to be prognostic markers for a better outcome of cancer patients. In immunotherapy of cancer, particularly in therapy with immune checkpoint inhibitors, eosinophils were even shown to be a potential predictive marker for a beneficial clinical response. A better understanding of their role in cancer progression will help to establish them as prognostic and predictive markers and to design strategies for targeting eosinophils.