Efficacy of immune checkpoint inhibitors in different types of melanoma.
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ABSTRACT:
SUBMITTER: Rossi E
PROVIDER: S-EPMC7872095 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The potential to harness the power of the immune system and effectively treat patients with metastatic melanoma is finally being realized with the advent of immune checkpoint inhibitors. These new therapies herald a new era in the treatment of melanoma with the potential to produce very durable responses and possible cure for a subset of patients, though bring with them challenges including novel toxicities and nonconventional response patterns. This article reviews the currently available immune checkpoint inhibitors, potential biomarkers to predict response and promising investigational approaches including combination therapies.
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Project description:In recent years, new strategies for treating melanoma have been introduced, improving the outlook for this challenging disease. One of the most important advances has been the development of immunotherapy. The better understanding of the role of the immunological system in tumor control has paved the way for strategies to enhance the immune response against cancer cells. Monoclonal antibodies (mAbs) against the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have demonstrated high activity in melanoma and other tumors. Ipilimumab, an anti CTLA-4 antibody, was the first drug of this class that was approved. Although the response rate with ipilimumab is low (less than 20% of patients have objective responses), 20% of patients have long survival, with similar results in the first and second line settings. Nivolumab and pembrolizumab, both anti PD-1 inhibitors, have been approved for the treatment of melanoma, with response rates of 40% and a demonstrated survival advantage in phase III trials. This has marked a new era in the treatment of metastatic melanoma and much research is now ongoing with other drugs targeting checkpoint inhibitors. In addition, the agonist of activating molecules on T cells and their combinations are being investigated. Herein we review the clinical development of checkpoint inhibitors and their approval for treatment of metastatic melanoma.
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Project description:Introduction:Immunotherapy with immune checkpoint inhibitors increases the overall survival of patients with metastatic melanoma regardless of their oncogene addicted mutations. However, no data is available from clinical trials of effective therapies in subgroups of melanoma patients that carry chronic infective diseases such as HIV. Evidences suggest a key role of the immune checkpoint molecules as a mechanism of immune escape not only from melanoma but also from HIV host immune response. Conclusion:In this article, firstly, we will describe the role of the immune checkpoint molecules in HIV chronic infection. Secondly, we will summarize the most relevant clinical evidences utilizing immune checkpoint inhibitors for the treatment of melanoma patients. Lastly, we will discuss the potential implications as well as the potential applications of immune checkpoint molecule-based immunotherapy in patients with melanoma and HIV infection.
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Project description:Torque Teno Virus (TTV) is a small, non-enveloped, single-stranded and circular DNA virus that infects the majority of the population worldwide. Increased levels of plasma TTV viral load have been observed in various situations of immune deficiency or dysregulation, and several studies have suggested that TTV levels may be inversely correlated with immune competence. The measurement of TTV viremia by qPCR has been proposed as a potential biomarker for the follow-up of functional immune competence in immunosuppressed individuals, particularly hematopoietic stem cell transplant recipients. We hypothesized that TTV viral load could be used as a prognostic marker of immune checkpoint inhibitor (ICI) efficacy, and therefore investigated the TTV viral load in melanoma patients treated with nivolumab or pembrolizumab before and after 6 months of treatment. In the present study, TTV viral load was not different in melanoma patients before anti-PD-1 introduction compared to healthy volunteers, was not modified by ICI treatment and did not allowed to distinguish patients with treatment-sensitive tumor from patients with treatment-resistant tumor.
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Project description:Modern immunotherapy together with targeted therapy has revolutionized the treatment of advanced melanoma. Inhibition of immune checkpoints significantly improved the median overall survival and gave hope to many melanoma patients. However, this treatment has three serious drawbacks: high cost, serious side effects, and an effectiveness limited only to approximately 50% of patients. Some patients do not derive any or short-term benefit from this treatment due to primary or secondary resistance. The response to immunotherapy depends on many factors that fall into three main categories: those associated with melanoma cells, those linked to a tumor and its microenvironment, and those classified as individual ontogenic and physiological features of the patient. The first category comprises expression of PD-L1 and HLA proteins on melanoma cells as well as genetic/genomic metrics such as mutational load, (de)activation of specific signaling pathways and epigenetic factors. The second category is the inflammatory status of the tumor: "hot" versus "cold" (i.e., high versus low infiltration of immune cells). The third category comprises metabolome and single nucleotide polymorphisms of specific genes. Here we present up-to-date data on those biological factors influencing melanoma response to immunotherapy with a special focus on signaling pathways regulating the complex process of anti-tumor immune response. We also discuss their potential predictive capacity.
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Project description:Immune checkpoint inhibitors (ICIs) therapy is a novel strategy for cancer treatments in recent years. However, it was observed that most patients treated with ICIs could not get benefit from the therapy, which led to the limitation of clinical application. Motivated by potent and durable efficacy of ICIs, oncologists endeavor to explore the mechanisms of resistance to ICIs and increase the drug sensitivity. It is known that heterogeneity of gut microbiome in populations may result in different outcomes of therapy. In xenograft model, bacteria in gut have been proved as a crucial factor regulating immunotherapy efficacy. And the similar phenomenon was obtained in patients. In this review, we summarized relevant advancements about gut microbiome and ICIs. Furthermore, we focused on modulatory function of gut microbiome in ICIs therapy and possible antitumor mechanism of specific commensals in ICIs treatment. We propose that gut microbiome is an important predictive factor, and manipulation of gut microbiome is feasible to elevate response rate in ICIs therapy.
| S-EPMC5870075 | biostudies-literature
Project description:Immunotherapy with immune checkpoint inhibitors is the standard of care in the treatment of advanced melanoma. Treatment outcome of these agents is less defined for the rare subtype of mucosal melanoma. In this single-institutional case series, the objective response rate was low at 11.8%, but durable response was seen, including a complete response to first-line ipilimumab and to second-line pembrolizumab. Survival remained poor; at the median follow-up of 10.1 months, the median progression-free survival and overall survival were 3.1 and 8.8 months respectively. Nevertheless, among the few responders, survival of up to 56+ months was observed. Other treatment strategies need to be explored to improve treatment outcome for this rare subtype.
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Project description:IntroductionAcral melanoma (AM) has different biological characteristics from cutaneous melanoma. Although systemic therapeutic strategies for advanced AM resemble those for advanced cutaneous melanoma, the evidence of the clinical use of immune checkpoint inhibitors (ICIs) for AM is still inadequate. We aimed to systematically analyze the therapeutic effects and safety profile of ICI treatments in advanced AM.MethodsThis systematic review was conducted in line with a previously registered protocol. Three electronic databases, conference abstracts, clinical trial registers, and reference lists of included articles were searched for eligible studies. The primary outcomes were therapeutic effects, and the secondary outcomes were the safety profiles.ResultsThis systematic review included six studies investigating anti-CTLA-4 immunotherapy, 12 studies investigating anti-PD-1 immunotherapy, one study investigating the combination therapy of anti-CTLA-4 and anti-PD-1, and one study investigating anti-PD-1 immunotherapy in combination with radiotherapy. In most studies investigating ipilimumab, the anti-CTLA-4 antibody, the objective response rate ranged from 11.4 to 25%, the median progression-free survival ranged from 2.1 to 6.7 months, and the median overall survival was more than 7.16 months. For studies discussing anti-PD-1 immunotherapy with nivolumab, pembrolizumab, or JS001, the objective response rate ranged from 14 to 42.9%, the median progression-free survival ranged from 3.2 to 9.2 months, and the median overall survival was more than 14 months. The combination therapy of anti-CTLA-4 and anti-PD-1 immunotherapy showed better efficacy with an objective response rate of 42.9% than single-agent therapy. The retrospective study investigating the combination therapy of anti-PD-1 immunotherapy and radiation showed no overall response. Few outcomes regarding safety were reported in the included studies.ConclusionsICIs, especially anti-CTLA-4 monoclonal antibodies combined with anti-PD-1 antibodies, are effective systematic treatments in advanced AM. However, there remains a lack of high-level evidence to verify their efficacy and safety and support their clinical application.
| S-EPMC7744720 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitors (ICIs) have shown remarkable success in treating skin cutaneous melanoma (SKCM); however, the response to treatment varies greatly between patients. Considering that the efficacy of ICI treatment is influenced by many factors, we selected the Fibrosheath interacting protein 2 (FSIP2) gene and systematically analyzed its potential to predict the efficacy of ICI treatment.MethodsPatient data were collected from an ICI treatment cohort (n = 120) and a The Cancer Genome Atlas (TCGA)-SKCM cohort (n = 467). The data were divided into an FSIP2-mutant (MT) group and FSIP2-wild-type (WT) group according to FSIP2 mutation status. In this study, we analyzed the patients' overall survival rate, tumor mutational burden (TMB), neoantigen load (NAL), copy number variation (CNV), cell infiltration data and immune-related genes. We used gene set enrichment analysis (GSEA) to delineate biological pathways and processes associated with the efficacy of immunotherapy.ResultsThe efficacy of ICI treatment of SKCM patients with FSIP2 mutation was significantly better than that of patients without FSIP2 mutation. The patients in the FSIP2-MT group had higher tumor immunogenicity and lower regulatory T cell (Treg) infiltration. Results of GSEA showed that pathways related to tumor progression (MAPK and FGFR), immunomodulation, and IL-2 synthesis inhibition were significantly downregulated in the FSIP2-MT group.ConclusionOur research suggests that the FSIP2 gene has the potential to predict the efficacy of ICI treatment. The high tumor immunogenicity and low Treg levels observed may be closely related to the fact that patients with FSIP2-MT can benefit from ICI treatment.
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Project description:Gut microbiota impacts responses to immune checkpoint inhibitors (ICI). High level of Faecalibacterium prausnitzii has been associated with a positive response to ICI in multiple cancer types. Here, we show in two independent cohorts of patients with non-small cell lung cancer and advanced melanoma that high level of F. prausnitzii at baseline is positively associated with a better clinical response to ICI. In a mouse preclinical model, we show that the F. prausnitzii strain EXL01, already in clinical development for Inflammatory Bowel Disease, restores the anti-tumor response to ICI in the context of antibiotic-induced microbiota perturbation at clinical and tumor transcriptomics level. In vitro, EXL01 strain enhances T cell activation in the presence of ICI. Interestingly, oral administration of EXL01 strain is not associated with a change in fecal microbiota diversity or composition suggesting a direct effect on immune cells in the small intestine.
2024-07-10 | GSE234818 | GEO