The Latest on Uveal Melanoma Research and Clinical Trials: Updates from the Cure Ocular Melanoma (CURE OM) Science Meeting (2019)

Chua, Vivian; Mattei, Jane; Han, Anna; Johnston, Lauren; LiPira, Kyleigh; Selig, Sara; Aplin, Andrew E.; Patel, Sapna

doi:10.1158/1078-0432.ccr-20-2536

Cited by 24 publications

(19 citation statements)

References 44 publications

(28 reference statements)

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“…Several clinical trials using new molecules, inhibitors alone or in combination are being developed based on preclinical work. MEK inhibitors when combined with dacarbazine or other chemotherapy agents failed to improve progression free survival in UM ( 226 ). However, new combination treatments co-targeting MEK with PKC, FAK, GNAQ/11 and other main pathways such as YAP have revealed promising new therapeutic vulnerabilities that can be exploited in a clinical manner (NCT03875820) ( 227 – 229 ).…”

Section: Conclusion Perspectives and Outstanding Questionsmentioning

confidence: 99%

Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy

et al. 2021

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Melanoma is the deadliest form of skin cancer. Although targeted therapies and immunotherapies have revolutionized the treatment of metastatic melanoma, most patients are not cured. Therapy resistance remains a significant clinical challenge. Melanoma comprises phenotypically distinct subpopulations of cells, exhibiting distinct gene signatures leading to tumor heterogeneity and favoring therapeutic resistance. Cellular plasticity in melanoma is referred to as phenotype switching. Regardless of their genomic classification, melanomas switch from a proliferative and differentiated phenotype to an invasive, dedifferentiated and often therapy-resistant state. In this review we discuss potential mechanisms underpinning melanoma phenotype switching, how this cellular plasticity contributes to resistance to both targeted therapies and immunotherapies. Finally, we highlight novel strategies to target plasticity and their potential clinical impact in melanoma.

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Section: Conclusion Perspectives and Outstanding Questionsmentioning

confidence: 99%

Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy

et al. 2021

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“…PV-10, a small molecule that accumulates in lysosomes inducing autolysis, can produce immunogenic cell death and therefore a T cell-mediated immune response against immunologically cold tumors, providing a rationale for the association with ICBs. Preliminary results were presented for 13 patients with stable disease (SD) in 62.5% and PR in 37.5% of patients [ 85 ]. Results from combination therapy with PV-10 and ICBs are awaited with interest.…”

Section: Immune Checkpoint Inhibitors: Retrospective Real-world Studies and Clinical Trialsmentioning

confidence: 99%

How to Make Immunotherapy an Effective Therapeutic Choice for Uveal Melanoma

Marseglia

Amaro

Solari

et al. 2021

Cancers

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Uveal melanoma (UM), though a rare form of melanoma, is the most common intraocular tumor in adults. Conventional therapies of primary tumors lead to an excellent local control, but 50% of patients develop metastases, in most cases with lethal outcome. Somatic driver mutations that act on the MAP-kinase pathway have been identified, yet targeted therapies show little efficacy in the clinics. No drugs are currently available for the G protein alpha subunitsGNAQ and GNA11, which are the most frequent driver mutations in UM. Drugs targeting the YAP–TAZ pathway that is also activated in UM, the tumor-suppressor gene BRCA1 Associated Protein 1 (BAP1) and the Splicing Factor 3b Subunit 1 gene (SF3B1) whose mutations are associated with metastatic risk, have not been developed yet. Immunotherapy is highly effective in cutaneous melanoma but yields only poor results in the treatment of UM: anti-PD-1 and anti-CTLA-4 blocking antibodies did not meet the expectations except for isolated cases. Here, we discuss how the improved knowledge of the tumor microenvironment and of the cross-talk between tumor and immune cells could help to reshape anti-tumor immune responses to overcome the intrinsic resistance to immune checkpoint blockers of UM. We critically review the dogma of low mutational load, the induction of immune-suppressive cells, and the expression of alternative immune checkpoint molecules. We argue that immunotherapy might still be an option for the treatment of UM.

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“…1B-2D, Table 3). When excluding uveal melanoma patients (n = 2), who are known to have lower response rates to anti-PD-1 10,11,12 , the ORR was 77%. The 6-month progression-free survival (PFS) rate for all patients was 63% and the median PFS (calculated from treatment start date to data cut off) was 20.3 months (95% CI, 5.2 -12.9) (Fig.…”

Section: Efficacymentioning

confidence: 99%

Targeting MDSCs using ATRA: a phase I/II clinical trial combining pembrolizumab and all-trans retinoic acid for metastatic melanoma

Tobin

Cogswell

Cates³

et al. 2021

Preprint

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Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) alters their activity and reduces MDSC frequency. This trial seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in metastatic melanoma patients. In 24 stage IV melanoma patients, treatment with pembrolizumab Q3W plus the supplemental treatment of ATRA orally for three days surrounding each of the first four pembrolizumab infusions effectively lowered the frequency of circulating PMN-MDSCs and enhanced melanoma-specific T cell activity. The combination was well tolerated. Median progression free survival was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response. Targeting MDSCs remains a promising mechanism to enhance the efficacy of anti-PD-1 therapies and this combination merits further investigation.

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The Latest on Uveal Melanoma Research and Clinical Trials: Updates from the Cure Ocular Melanoma (CURE OM) Science Meeting (2019)

Cited by 24 publications

References 44 publications

Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy

Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy

How to Make Immunotherapy an Effective Therapeutic Choice for Uveal Melanoma

Targeting MDSCs using ATRA: a phase I/II clinical trial combining pembrolizumab and all-trans retinoic acid for metastatic melanoma

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