Research Highlight |
Featured
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Research Highlight |
Personalized neoantigen mRNA vaccine mitigates melanoma recurrence
- David Killock
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Review Article |
BRAF — a tumour-agnostic drug target with lineage-specific dependencies
Various BRAF alterations are found and function as oncogenic drivers across diverse cancer types. BRAF inhibitor-based therapy has improved outcomes for patients with cancers harbouring BRAFV600 mutations, although resistance develops in most, and the current inhibitors are not effective against other types of BRAF alterations. In this Review, the authors describe the mechanisms underlying oncogenic BRAF signalling, as well as pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. They also discuss novel RAF inhibitors and drug combinations designed to overcome these resistance mechanisms and/or expand the applicability of molecularly targeted therapy to a broader range of BRAF-mutant cancers.
- Aphrothiti J. Hanrahan
- , Ziyu Chen
- & David B. Solit
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Review Article |
Tumour-infiltrating lymphocyte therapy for patients with advanced-stage melanoma
Despite dramatic progress over the past decade, only around 50% of patients with advanced-stage melanoma derive durable benefit from immune-checkpoint inhibitors (ICIs) and/or BRAF and MEK (BRAF/MEK) inhibitors. Over the past few years, adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) has demonstrated encouraging efficacy including in patients with disease progression on ICIs or BRAF/MEK inhibitors. In this Review, the authors summarize the role of TIL therapies in the management of these patients and describe future research strategies that might improve safety or efficacy.
- Sebastian Klobuch
- , Tom T. P. Seijkens
- & John B. A. G. Haanen
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Review Article |
Personalizing neoadjuvant immune-checkpoint inhibition in patients with melanoma
Neoadjuvant immune-checkpoint inhibition is a promising emerging treatment strategy that potentially enables patients with a good response to initial therapy to avoid further treatment and the associated toxicity risks, while also identifying those who might require treatment escalation. In this Review, the authors describe treatment personalization strategies based on the initial response to one or more neoadjuvant immune-checkpoint inhibitors and consider the potential to expand this approach beyond patients with melanoma.
- Minke W. Lucas
- , Judith M. Versluis
- & Christian U. Blank
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Review Article |
Therapy with oncolytic viruses: progress and challenges
Oncolytic viruses (OVs) provide a novel cancer treatment strategy, with a mechanism of action and toxicity profiles that are distinctly different to those of more traditional therapies. Thus far, four OVs have entered clinical use globally, yet only talimogene laherparepvec (T-VEC) has entered widespread clinical use. In this Review, the authors describe the clinical and regulatory experience with T-VEC thus far, and how this can guide the development of novel OVs. Discussions of a range of novel OVs with the potential for clinical implementation in the near future are also provided.
- Sophia Z. Shalhout
- , David M. Miller
- & Howard L. Kaufman
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Review Article |
Advances in the clinical management of uveal melanoma
Although almost all patients with uveal melanoma have localized disease at diagnosis, and despite effective treatment of the primary tumour, metastatic recurrence is common and holds a dismal prognosis. Unlike its cutaneous counterpart, therapeutic advances for uveal melanoma have not been forthcoming, although the recent approval of the first systemic therapy for this disease has ushered in a new era of hope. This Review summarizes the biology of uveal melanoma and the management of primary disease, including molecular risk classification, adjuvant therapy and follow-up strategies. The discussion is then focused on the established and emerging regional and systemic treatments for metastatic uveal melanoma.
- Richard D. Carvajal
- , Joseph J. Sacco
- & Sophie Piperno-Neumann
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News & Views |
Personalizing the approach to neoadjuvant therapy: a promising path to improving outcomes of resectable melanoma
Clinical trials of neoadjuvant therapy for melanoma have expanded rapidly over the past several years. Preliminary data demonstrate the prognostic value of pathological response, which might have clinical implications for refining the roles of surgery and adjuvant therapy. These clinical questions are under active investigation across many ongoing clinical trials.
- Giorgos C. Karakousis
- & Tara C. Mitchell
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Viewpoint |
Optimal systemic therapy for high-risk resectable melanoma
Immune-checkpoint inhibitors and BRAF-targeted therapy have revolutionized the treatment of advanced-stage, unresectable melanoma and have been successfully transitioned into the resectable disease setting as (neo)adjuvant treatments. The expanding range of treatment options available for resectable high-risk melanoma raises questions over selection of the optimal therapeutic strategy and agents for each individual. Furthermore, the use of perioperative therapy has potentially important implications for the management of patients who have disease recurrence. In this Viewpoint, we asked four expert investigators who have been involved in the key studies of perioperative systemic therapies for their perspectives on the optimal management of patients with high-risk melanoma.
- Alexander M. M. Eggermont
- , Omid Hamid
- & Jason J. Luke
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News & Views |
Gut microbes as biomarkers of ICI response — sharpening the focus
Two recent large-cohort studies reinforce the potential predictive capability of gut microbiota for immune-checkpoint inhibitor response and toxicities in patients with melanoma. However, additional investigations are required to understand the mechanistic underpinnings of this complex multifaceted relationship, and how it can be exploited for personalized cancer care.
- Neal Bhutiani
- & Jennifer A. Wargo
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Review Article |
Immune-checkpoint inhibitors: long-term implications of toxicity
Immune-checkpoint inhibitors (ICIs) have dramatically improved the outcomes of patients with advanced-stage solid tumours, including the potential for long-term remission in a subset. However, long-term follow-up data reveal a risk of chronic toxicities from these agents, which can have important quality-of-life implications. In this Review, the authors describe the current level of evidence of chronic toxicities of ICIs and their implications for patients
- Douglas B. Johnson
- , Caroline A. Nebhan
- & Justin M. Balko
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News & Views |
First clinical proof-of-concept that FMT can overcome resistance to ICIs
An unfavourable gut bacterial composition has been shown to reduce the likelihood of clinical benefit from immune-checkpoint inhibitors (ICIs). The results of two first-in-human studies of faecal microbiota transplantation in patients with melanoma refractory to anti-PD-1 antibodies validate preclinical evidence that this approach can improve the gut microbiota and overcome resistance to ICIs; however, many questions remain.
- Arielle Elkrief
- & Bertrand Routy
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Research Highlight |
Pathological correlates and predictive biomarkers for neoadjuvant ICIs in melanoma
- David Killock
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News & Views |
Cancer vaccine induces potent T cell responses — but is it enough?
Tumour-associated antigens are an attractive therapeutic target in immuno-oncology. Here, the exploratory analyses of T cell responses and preliminary clinical outcomes of the Lipo-MERIT trial of a melanoma vaccine are discussed in the context of prior efforts to harness the immunogenicity of such antigens for antitumour immunity.
- Anjali Rohatgi
- & John M. Kirkwood
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News & Views |
Biology confirmed but biomarkers elusive in melanoma immunotherapy
Liu et al. report data from the largest sequencing analysis of tumour material from patients with metastatic melanoma receiving immune-checkpoint inhibitors. These data confirm the correlations between baseline immune infiltrate and treatment response, but also demonstrate inconsistent associations of tumour mutational burden, specific gene mutations and previously described gene expression patterns with clinical outcomes.
- Jason J. Luke
- & Paolo A. Ascierto
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Research Highlight |
Paradoxical roles of mutational load as a determinant of anticancer immunity
- David Killock
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Comment |
No other interest can take precedence — a patient’s perspective on oncology drug development
My husband’s diagnosis with melanoma and our struggle to access effective therapy challenged what I had learnt about medical research. I have since founded a patient network, becoming a vocal advocate for patient-centric drug development. Herein, I discuss some of the lessons I have learnt.
- Bettina Ryll
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Review Article |
Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance
Immune-checkpoint inhibitors (ICIs) have dramatically improved the survival of patients with certain forms of cancer; however, these agents also have adverse effects that are often quite different to those of more traditional cancer therapies. In this Review, the authors describe the epidemiology, treatment and management of the various immune-related adverse events that can occur in patients receiving ICIs.
- Filipe Martins
- , Latifyan Sofiya
- & Michel Obeid
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Review Article |
Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNγ pathways
The authors of this Review propose a new model in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the process of therapeutic resistance development in patients with melanoma.
- Xue Bai
- , David E. Fisher
- & Keith T. Flaherty
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Research Highlight |
Signatures IMPRES and might turn the TIDE in predicting responses
- David Killock
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News & Views |
The new era of adjuvant therapies for melanoma
New treatment options for patients with resected stage III melanoma have been established with the publication of the results of four pivotal randomized clinical trials, resulting in three drug approvals, with a forth expected, all within only 4 years. Herein, we put these advances into context.
- Alexander M. M. Eggermont
- , Caroline Robert
- & Antoni Ribas
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Year in Review |
Moving treatments earlier to move further forwards
In 2017, results from phase III trials demonstrated the impressive safety and efficacy of adjuvant targeted and immune therapies in patients with resectable stage III–IV melanoma, and raised questions about the surgical management of patients with microscopic sentinel-lymph-node metastases. For patients with unresectable disease, new overall survival data added to the debate about the relative benefits of single-agent anti-PD-1 versus combined anti-PD-1 and anti-CTLA-4 immunotherapy.
- Michael A. Davies
- & Keith T. Flaherty
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