Featured
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Article |
Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma
In a post hoc analysis of the phase 2 PRADO trial, baseline emotional distress was associated with reduced clinical responses in patients with stage III melanoma treated with neoadjuvant ipilimumab and nivolumab.
- Itske Fraterman
- , Irene L. M. Reijers
- & Lonneke V. van de Poll-Franse
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Article
| Open Access
Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial
In this pre-specified interim analysis, patients with resected stage IIB/C melanoma who received adjuvant nivolumab had significantly prolonged recurrence-free survival compared to placebo-treated patients, providing another treatment option for this population.
- John M. Kirkwood
- , Michele Del Vecchio
- & Georgina V. Long
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Article |
Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial
In patients with advanced melanoma, fecal microbiota transplantation from healthy donors combined with the anti-PD-1 inhibitors nivolumab or pembrolizumab was well tolerated with an encouraging objective response rate of 65% in the first-line treatment setting.
- Bertrand Routy
- , John G. Lenehan
- & Saman Maleki Vareki
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Article
| Open Access
Multi-organ landscape of therapy-resistant melanoma
Genomic analyses in a rapid autopsy cohort study of patients with melanoma identify the genetic and transcriptomic landscape of melanoma with acquired resistance to MAPK inhibitor and immune checkpoint blockade therapies, providing insights for the potential improvement of therapeutic strategies.
- Sixue Liu
- , Prashanthi Dharanipragada
- & Roger S. Lo
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Article
| Open Access
Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results
In an interim analysis of a phase 1 trial of concurrent intrathecal and intravenous anti-PD1 delivery in patients with leptomeningeal disease and melanoma, treatment was feasible and well-tolerated with no dose-limiting toxicities.
- Isabella C. Glitza Oliva
- , Sherise D. Ferguson
- & Michael A. Davies
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News & Views |
Using genetics to predict toxicity of cancer immunotherapy
A variant of the IL7 gene predicts the toxicity of checkpoint inhibitors in patients with cancer, via a mechanism shared with autoimmune diseases — which could inform biomarker and treatment strategies in both of these contexts.
- Caroline Robert
- , Stéphan Vagner
- & Xavier Mariette
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Article
| Open Access
IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma
Genetic analyses in a cohort of patients with melanoma receiving immunotherapy reveal that variants in IL7 are associated with immune-related adverse events and highlight the role of B cells in mediating toxicity.
- Chelsea A. Taylor
- , Robert A. Watson
- & Benjamin P. Fairfax
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Article |
Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome
A prospective analysis of gut microbiome signatures in patients treated with neoadjuvant immunocheckpoint blockade for high risk resectable metastatic melanoma identifies new links between microbiota signatures, dietary intake and systemic inflammation in shaping the response and toxicity to immunotherapy.
- Rebecca C. Simpson
- , Erin R. Shanahan
- & Georgina V. Long
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Article |
Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial
Results from the PRADO extension cohort of the OpACIN-neo trial show that pathologic response rate to neoadjuvant ipilimumab and nivolumab can be used as a criterion for personalization of further treatment in stage III nodal melanoma, with the potential to reduce treatment morbidity and increase patient quality of life.
- Irene L. M. Reijers
- , Alexander M. Menzies
- & Christian U. Blank
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Article |
Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1
Integrated analysis of microbiome and host cell transcriptional data on clinically annotated cohorts of patients with melanoma who were treated with anti-programmed cell death protein-1, uncovers new associations of streptococcus species with immune-related adverse effects and finds consistent microbiome associations with clinical outcomes.
- John A. McCulloch
- , Diwakar Davar
- & Amiran K. Dzutsev
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Article |
T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma
Clonally diverse and activated memory CD4+ T cells at baseline are associated with the development of severe immune-related adverse events, irrespective of the affected organ system, in patients with melanoma treated with immune checkpoint inhibitors.
- Alexander X. Lozano
- , Aadel A. Chaudhuri
- & Aaron M. Newman
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Research Highlight |
HIV and skin cancer risk
People with HIV who delay initiation of anti-retroviral therapy have permanent loss of memory T cells in the skin, which may explain their increased risk of skin cancer.
- Karen O’Leary
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Article
| Open Access
A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma
A first-in-class immune-modulating IDO/PD-L1-targeting vaccine combined with nivolumab in a phase 1/2 trial achieved very promising clinical activity and long-lasting immune responses in patients with advanced melanoma.
- Julie Westerlin Kjeldsen
- , Cathrine Lund Lorentzen
- & Inge Marie Svane
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Article |
Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB–IVM1a melanoma: a randomized, open-label, phase 2 trial
Intralesional injection of an oncolytic virus prior to surgery shows favorable clinical activity over surgery alone in patients with locally advanced, resectable melanoma, supporting further evaluation in the neoadjuvant setting for this population.
- R. Dummer
- , D. E. Gyorki
- & M. I. Ross
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Letter |
Evolution of delayed resistance to immunotherapy in a melanoma responder
Genetic and protein expression analyses of serially collected tumor biopsies from a patient with melanoma treated with immune checkpoint inhibitors provide insights into tumor microenvironment changes that occur during treatment resistance.
- David Liu
- , Jia-Ren Lin
- & Genevieve M. Boland
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Article |
Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC)
A pooled analysis of neoadjuvant immunotherapy trials in melanoma shows that the degree of pathological response associates with patient survival and might represent a surrogate marker for long-term outcomes.
- Alexander M. Menzies
- , Rodabe N. Amaria
- & Georgina V. Long
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Letter |
Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma
Long-term outcomes and biomarker analyses of two neoadjuvant immunotherapy clinical trials in melanoma patients support the clinical benefit of this treatment approach and uncover prognostic correlates of response.
- E. A. Rozeman
- , E. P. Hoefsmit
- & C. U. Blank
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Article |
Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma
Personalized neoantigen vaccination in patients with melanoma elicits durable and specific memory T cell clones that have cytotoxic gene signatures and can diversify to include nonvaccine neoantigen specificities.
- Zhuting Hu
- , Donna E. Leet
- & Patrick A. Ott
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Letter |
Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i
Clinical activity and biomarker analysis from the COMBI-i trial evaluating PD-1, BRAF and MEK inhibition in patients with metastatic melanoma demonstrate high response rates and uncover molecular correlates of long-term treatment benefit.
- Reinhard Dummer
- , Celeste Lebbé
- & Georgina V. Long
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Letter |
Human–computer collaboration for skin cancer recognition
A systematic evaluation of the value of AI-based decision support in skin tumor diagnosis demonstrates the superiority of human–computer collaboration over each individual approach and supports the potential of automated approaches in diagnostic medicine.
- Philipp Tschandl
- , Christoph Rinner
- & Harald Kittler
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Letter |
Common germline variants of the human APOE gene modulate melanoma progression and survival
Heritable APOE variants in patients with melanoma influence anti-tumor immunity and modulate metastatic progression and response to immunotherapy.
- Benjamin N. Ostendorf
- , Jana Bilanovic
- & Sohail F. Tavazoie
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Brief Communication |
Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors
In a retrospective analysis of data from four phase 3 clinical trials, elevated baseline serum IL-8 levels were associated with worse clinical outcomes in patients with multiple tumor types treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combinatorial therapy.
- Kurt A. Schalper
- , Michael Carleton
- & Ignacio Melero
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Resource |
Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy
Genetically engineered mouse models representing the spectrum of human cutaneous melanoma provide a platform for studying clinical responses to immunotherapy.
- Eva Pérez-Guijarro
- , Howard H. Yang
- & Glenn Merlino
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Letter |
Peripheral CD8+ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma
Transcriptomic analysis of peripheral CD8+ T cells in a cohort of patients with metastatic melanoma receiving checkpoint inhibitors shows that the number of large clones early post-treatment is strongly associated with six-month clinical outcome.
- Benjamin P. Fairfax
- , Chelsea A. Taylor
- & Mark R. Middleton
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Matters Arising |
Reply to: ‘IMPRES does not reproducibly predict response to immune checkpoint blockade therapy in metastatic melanoma’
- Noam Auslander
- , Joo Sang Lee
- & Eytan Ruppin
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Article
| Open Access
Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma
Analysis of fully clinically annotated and sequenced melanoma tumor samples collected before anti-PD1 treatment suggests that determinants of response differ on the basis of previous anti-CTLA4 therapy, and that tumor mutational burden may not be a strong predictor of response across melanoma subtypes.
- David Liu
- , Bastian Schilling
- & Dirk Schadendorf
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Letter |
Clonal replacement of tumor-specific T cells following PD-1 blockade
Following anti-PD-1 therapy in patients with basal or squamous cell carcinoma, the CD8+ T cell response largely consists of an expanded and exhausted repertoire of new T cell clones.
- Kathryn E. Yost
- , Ansuman T. Satpathy
- & Howard Y. Chang
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Letter |
A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis
Deep molecular profiling of a single case of severe anti-PD-1-induced neurotoxicity shows oligoclonal cytotoxic memory CD4+ T cells are enriched in inflamed brain tissue.
- Douglas B. Johnson
- , Wyatt J. McDonnell
- & Justin M. Balko
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Letter |
Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma
Triple therapy combining BRAF and MEK inhibitors with immune checkpoint blockade may benefit a subset of patients with BRAF V600-mutated metastatic melanoma.
- Antoni Ribas
- , Donald Lawrence
- & Omid Hamid
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Letter |
Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma
A randomized phase 2 trial testing triple combination of BRAF, MEK and PD-1 inhibition as first-line therapy in patients with BRAF-mutant melanoma shows durable responses and encouraging progression-free survival.
- Paolo Antonio Ascierto
- , Pier Francesco Ferrucci
- & Antoni Ribas
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Letter |
Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas
Rearrangements in MAP3K8 respond to MEK inhibition and represent the most common genetic driver in pediatric spitzoid melanoma, and in some adult melanomas lacking other MAPK alterations and for which clinical testing is warranted.
- Scott Newman
- , Liying Fan
- & Armita Bahrami
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Letter |
A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma
Neoadjuvant PD-1 blockade in patients with resectable melanoma followed by adjuvant maintenance results in early immunological effects driving clinical benefit and reveals transcriptional and genomic mechanisms of response.
- Alexander C. Huang
- , Robert J. Orlowski
- & Tara C. Mitchell
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Brief Communication |
Ultraviolet radiation–induced DNA damage is prognostic for outcome in melanoma
Mutational signatures in melanoma are associated with prognostic features in patients and suggest distinct disease etiologies associated with the influence of different wavelengths of ultraviolet radiation.
- Lucas D. Trucco
- , Piyushkumar A. Mundra
- & Richard Marais
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Perspective |
Is earlier better for melanoma checkpoint blockade?
A neoadjuvant approach using combined anti-CTLA4/anti-PD1 treatment prior to lymph node surgery is evaluated in two phase I trials of later stage melanoma finding this a therapeutic angle worth pursuing.
- Caroline Robert
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Article |
Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma
The translation initiation complex mediates tumor immune escape in melanoma by controlling STAT1 mRNA levels and T lymphocyte–induced PD-L1 expression.
- Michaël Cerezo
- , Ramdane Guemiri
- & Caroline Robert
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Letter |
Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma
Neoadjuvant combination treatment with nivolumab and ipilimumab in patients with high-risk melanoma results in higher response rates than nivolumab monotherapy and warrants future optimization of dosing regimens to preserve efficacy while limiting toxicity.
- Rodabe N. Amaria
- , Sangeetha M. Reddy
- & Jennifer A. Wargo
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Letter |
Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma
Neoadjuvant combination immunotherapy in patients with advanced melanoma shows favorable activity over adjuvant treatment and warrants future evaluation with modified dosing schedules to reduce treatment-related adverse events.
- Christian U. Blank
- , Elisa A. Rozeman
- & Ton N. Schumacher
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News & Views |
The intestinal microbiome influences checkpoint blockade
Studies in metastatic melanoma, non-small-cell lung carcinoma and renal cell carcinoma indicate certain bacteria within the gut microbiota enhance clinical responses to checkpoint blockade.
- Cynthia L Sears
- & Drew M Pardoll
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Article |
Noncanonical hedgehog pathway activation through SRF–MKL1 promotes drug resistance in basal cell carcinomas
A large proportion of basal cell carcinomas develop resistance independently of the canonical mutations in genes encoding hedgehog pathway components. An unbiased analysis investigating alternative pathways of resistance uncovers the role of cytoskeletal signaling in driving noncanonical activation of hedgehog signaling through nuclear translocation of SRF and MKL1. These results advance understanding of the mechanisms underlying drug resistance and provide new actionable insights for clinical translation.
- Ramon J Whitson
- , Alex Lee
- & Anthony E Oro
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Article |
An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer
Resistance to ERK signaling inhibitors in BRAFV600E-mutant melanomas and lung cancers is achieved by parallel convergent mechanisms, including amplification of the mutant allele in extrachromosomal elements, that allow tumors to adapt while maintaining their intratumor heterogeneity. Intermittent treatment with a combination of RAF, MEK and ERK inhibitors imposes a higher selective pressure than sequential therapy and produces the strongest antitumor effects while minimizing toxicity. These findings warrant evaluating the effectiveness of this combinatorial regimen in patients, to improve treatment responses and delay the emergence of drug resistance.
- Yaohua Xue
- , Luciano Martelotto
- & Piro Lito
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Letter |
Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma
Mutation or downregulation of cohesin components confer ERK reactivation and resistance to BRAF or MEK inhibitors in melanoma cells expressing BRAF or NRAS activating mutations.
- Che-Hung Shen
- , Sun Hye Kim
- & Bin Zheng
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Article |
An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation
Conditional expression of the most common somatic gain-of-function Ezh2 mutation in mouse models of melanoma and lymphoma reveals insight into its cooperation with other oncogenic events and its effects on the epigenome.
- George P Souroullas
- , William R Jeck
- & Norman E Sharpless
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News & Views |
A liquid biopsy for cancer immunotherapy
Human T cells that target tumor-specific mutations are attractive for cancer immunotherapy, but obtaining these T cells is challenging. A new study shows that tumor mutation–specific T cells can be isolated from the peripheral blood of patients with melanoma.
- Ton N Schumacher
- & Wouter Scheper
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Resource |
Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers
Understanding tumor metastasis is crucial to developing more effective cancer therapies. Here McCreery et al. analyzed the mutational profile of metastases from chemically induced skin tumors in mice and found that parallel evolution of synchronously disseminated tumor cells underlies most metastasis.
- Melissa Q McCreery
- , Kyle D Halliwill
- & Allan Balmain
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Letter |
High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma
Ton Schumacher and colleagues show that melanoma patients have CD4+ T cells reactive to mutated tumor antigens.
- Carsten Linnemann
- , Marit M van Buuren
- & Ton N M Schumacher
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News & Views |
Targeting RAF-MEK-ERK kinase-scaffold interactions in cancer
The RAS-RAF-MEK-ERK signaling kinase pathway has been the focus of intense cancer drug development efforts because of its central role in tumor cell proliferation and survival. Although inhibitors of RAF and MEK provide therapeutic validation, tumor resistance challenges their effectiveness. Targeting scaffolding proteins such as IQGAP1 may be a new approach (pages 626–630).
- Darrin D Stuart
- & William R Sellers
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Letter |
IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase–driven tumors
The MAPK cascade scaffolding protein IQGAP1, although dispensable for normal epithelial homeostasis, is required for RAS- and RAF-driven tumorigenesis in mouse tumor models. Accordingly, peptide-specific disruption of the interaction between IQGAP1 and ERK1/2 can bypass acquired resistance of vemurafenib-treated BRAF-mutant melanomas and extend the life span of tumor-bearing mice.
- Katherine L Jameson
- , Pawel K Mazur
- & Paul A Khavari
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Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma
Antitumor duality of ApoE