📬 Melanoma Intelligence Digest — Week 2026-W39
Real-world nivolumab-relatlimab and flipped-dose ipilimumab-nivolumab in brain metastases headline the melanoma week, alongside a Nature study of PLA2G2D-expressing macrophages in tumor-draining lymph nodes, an AP-1 network plasticity paper, RP1 plus nivolumab FDA approval discussion, and a basal cell carcinoma photodynamic therapy approval.
⚡ TL;DR
🐦 Twitter / 🦋 Bluesky
- Nature study: PLA2G2D-producing macrophages in tumor-draining lymph nodes brake tumor-specific T cells before they reach the melanoma — Tumor-draining lymph nodes from melanoma patients contained immune cells, mainly macrophages, producing high levels of the enzyme PLA2G2D, located near activated CD8+ T cells and associated with poorer outcomes
- AP-1 network interactions shape melanoma cell state plasticity in new Cell Reports paper — A Cell Reports paper reports that cell state plasticity in melanoma is shaped by co-regulated, competitive, configurable interactions within the AP-1 network
- Serum p40 rises before immune-related adverse events and its neutralization uncouples toxicity from checkpoint efficacy — Proteomic serum analysis in metastatic melanoma patients on anti-PD-1 plus anti-CTLA-4 identified an early significant increase of p40, a subunit of IL-12/IL-23, before clinically apparent irAEs, and it was not associated with checkpoint blockade efficacy
Full details below ↓
📄 What's Being Published
Dual checkpoint blockade beyond clinical trials: Real-world experience with nivolumab-relatlimab in advanced melanoma. — Asher Nethanel et al., Eur J Cancer
A total of 117 patients were treated with first-line nivolumab-relatlimab across 10 Israeli centers; the cohort was older and clinically frailer than pivotal trial populations, with a median age of 75 years and 38% aged 80 or older. The overall response rate was 69.8%, including a complete response rate of 43.6%, with a median PFS of 18.6 months and a 12-month OS of 74.1% (median OS and median MSS not reached). Grade 3–4 adverse events occurred in 11% of patients and treatment discontinuation due to toxicity in 14.5%, predominantly among those aged 80 or older; liver and/or bone metastases and prior neo- or adjuvant therapy were associated with inferior outcomes, and a higher-than-anticipated rate of neurologic toxicity was observed.
Clinical bottom line: In an older, frailer Israeli real-world cohort, first-line nivolumab-relatlimab delivered a 69.8% response rate with only 11% grade 3–4 toxicity, supporting its frontline use while flagging liver/bone metastases, prior adjuvant therapy, and unexpected neurologic toxicity as caution points.
Flipped versus traditional nivolumab plus ipilimumab dosing in patients with melanoma brain metastases. — Björkström Karl et al., Eur J Cancer
This retrospective analysis of 189 patients with melanoma brain metastases at two Swedish university hospitals compared NIVO3 + IPI1 (n = 54) against NIVO1 + IPI3 (n = 135); more patients completed all four induction doses with the flipped schedule (50.0% vs 30.4%, p = 0.011), and grade 3–4 immune-related adverse events were numerically lower (29.6% vs 43.0%, p = 0.090). Intracranial ORR was 44.4% vs 30.2% (p = 0.065) and global ORR 42.6% vs 29.2% (p = 0.080). In adjusted analyses, flipped dosing was associated with longer PFS (aHR 0.56, 95% CI 0.38–0.83, p = 0.004) and OS (aHR 0.54, 95% CI 0.35–0.83, p = 0.005).
Clinical bottom line: Flipped nivolumab 3 mg/kg plus ipilimumab 1 mg/kg dosing in melanoma brain metastases let twice as many patients finish induction and was associated with halved hazards for progression and death, making the lower-ipilimumab schedule a defensible real-world choice pending prospective confirmation.
🗂 Every paper considered this week, including the ones that didn’t make it →
🗣️ What People Were Discussing This Week
How these are chosen: filtered for clinical relevance, grouped by the new development discussed, then ordered by engagement (bookmarks and reposts).
Nature study: PLA2G2D-producing macrophages in tumor-draining lymph nodes brake tumor-specific T cells before they reach the melanoma
A population of immune cells, mainly macrophages, producing high levels of PLA2G2D was identified in tumor-draining lymph nodes from melanoma patients; these cells were located close to activated CD8+ T cells and were associated with poorer outcomes. In laboratory and mouse studies, PLA2G2D acted as an immune brake, limiting the early expansion of tumor-specific T cells, and blocking it increased the number of cancer-fighting T cells expanding in lymph nodes, entering the bloodstream, and reaching the tumor. Blocking PLA2G2D alongside PD-1 checkpoint inhibition produced additive or synergistic antitumor effects in preclinical models, suggesting the two pathways suppress T cells through distinct mechanisms. The central question is whether immune suppression beginning in the tumor-draining lymph node — rather than the tumor itself — means lymph-node-directed targets like PLA2G2D should be combined with PD-1 blockade in early melanoma trials.
Discussed by: @PatrickHwuMD, @EladSharonMD, @Immune_News
Sources cited: PLA2G2D in tumour-draining lymph nodes regulates anti-tumour immunity (Nature, 2026) · Cell Press
AP-1 network interactions shape melanoma cell state plasticity in new Cell Reports paper
A Cell Reports paper led by Yonatan Degefu at UVABME reports that cell state plasticity in melanoma is shaped by co-regulated, competitive, configurable interactions within the AP-1 network. A separate report in melanoma under dabrafenib finds that drug-tolerant persisters accumulate sphingomyelin and cholesterol without changing membrane fluidity or tension. The open question is whether mapping the AP-1 transcription factor network provides a tractable handle on the phenotype switching that underlies targeted therapy escape in melanoma.
Discussed by: @MFallahiSichani, @cdrjournal
Sources cited: Cell Press
Serum p40 rises before immune-related adverse events and its neutralization uncouples toxicity from checkpoint efficacy
Proteomic analysis of serum from metastatic melanoma patients on anti-PD-1 plus anti-CTLA-4 identified an early, significant increase of p40 — a subunit of IL-12/IL-23 — prior to the onset of clinically apparent immune-related adverse events, and this rise was not associated with checkpoint blockade efficacy. In mouse models mimicking patient irAEs, p40 neutralization prevented checkpoint-induced toxicity without compromising antitumor T cell immunity, including the establishment of tumor-specific responses, indicating that these mechanisms can be uncoupled. A separate short report of 23 patients found no major tumor microenvironment differences between frail and non-frail patients and comparable OS by frailty status (P=0.538). Clinicians are debating whether serum p40 is ready for prospective testing as a pre-symptomatic biomarker and whether anti-p40 agents could serve as the first toxicity-sparing addition to combination checkpoint blockade.
Discussed by: @EladSharonMD, @OncoAlert
Sources cited: JITC
🔥 Top Ranked Tweets
Vumedi Oncology @VuMediHemOnc
🚨 FDA APPROVAL: RP1 (vusolimogene oderparepvec-wtpg) + nivolumab offers a new treatment option for anti-PD-1 refractory melanoma.
⚕️ Dr. Gino In reviews the IGNYTE data and key considerations for clinical use.
🎥 Watch on Vumedi: https://t.co/yOHk23heKh
#Melanoma #FDAApproval https://t.co/eLXsPHvc1p
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Dr. Patrick Hwu @PatrickHwuMD
#ScienceSaturday What if #cancer starts weakening T cells before they even reach the tumor?
A new study published in @Nature suggests that an important part of cancer’s immune suppression may happen outside the #tumor itself, in nearby lymph nodes where cancer-fighting T cells are activated and prepared to respond.
🔬 Researchers studied tumor-draining #lymph nodes from patients with melanoma and identified a population of immune cells, mainly macrophages, producing high levels of an enzyme called PLA2G2D. These cells were found close to activated CD8+ T cells and were associated with poorer outcomes.
In laboratory and mouse studies, PLA2G2D acted like an immune brake, limiting the early expansion of tumor-specific T cells. When researchers blocked it, more cancer-fighting T cells expanded in the lymph nodes, entered the bloodstream and ultimately reached the tumor.
Even more interesting, blocking PLA2G2D alongside PD-1 checkpoint inhibition produced additive or synergistic antitumor effects in preclinical models, suggesting the two pathways may suppress #Tcells in different ways.
💡 Why does this matter? We often focus on overcoming immune suppression inside the tumor. This study suggests there may also be important immune “checkpoints” in the lymph nodes where antitumor responses begin.
There is still more work to do before this approach can be tested as a treatment in patients, but understanding these early barriers could reveal new ways to help more tumor-specific T cells make it into the fight. @AvanKrimpen_ @R_Stadhouders @bart_lambrecht @ErasmusMC @tmu2010 @UTokyo_News_en @NatureComms @NatureMedicine
Read the study: https://t.co/qRABB2nQpo
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Elad Sharon @EladSharonMD
RT @PatrickHwuMD: #ScienceSaturday What if #cancer starts weakening T cells before they even reach the tumor?
A new study published in @Nature suggests that an important part of cancer’s immune suppression may happen outside the #tumor itself, in nearby lymph nodes where cancer-fighting T cells are activated and prepared to respond.
🔬 Researchers studied tumor-draining #lymph nodes from patients with melanoma and identified a population of immune cells, mainly macrophages, producing high levels of an enzyme called PLA2G2D. These cells were found close to activated CD8+ T cells and were associated with poorer outcomes.
In laboratory and mouse studies, PLA2G2D acted like an immune brake, limiting the early expansion of tumor-specific T cells. When researchers blocked it, more cancer-fighting T cells expanded in the lymph nodes, entered the bloodstream and ultimately reached the tumor.
Even more interesting, blocking PLA2G2D alongside PD-1 checkpoint inhibition produced additive or synergistic antitumor effects in preclinical models, suggesting the two pathways may suppress #Tcells in different ways.
💡 Why does this matter? We often focus on overcoming immune suppression inside the tumor. This study suggests there may also be important immune “checkpoints” in the lymph nodes where antitumor responses begin.
There is still more work to do before this approach can be tested as a treatment in patients, but understanding these early barriers could reveal new ways to help more tumor-specific T cells make it into the fight. @AvanKrimpen_ @R_Stadhouders @bart_lambrecht @ErasmusMC @tmu2010 @UTokyo_News_en @NatureComms @NatureMedicine
Read the study: https://t.co/qRABB2nQpo
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Yago Garitaonaindía @YGaritaonaindia
RT @PatrickHwuMD: 🧬 #ScienceSaturday What if a T cell didn’t have to recognize #cancer to help destroy it?
We often think of cancer-fighting T cells as highly specific hunters that recognize a particular target on a cancer cell and attack it.
But a new study published in @NatImmunol suggests T cells may have another way to fight tumors.
🔬 Researchers found that activating “bystander” CD8+ T cells inside tumors, including #Tcells originally trained to recognize viruses, not cancer, was enough to trigger tumor destruction in experimental models.
Instead of directly recognizing and killing the cancer cells themselves, these activated T cells released powerful immune signals including interferon-gamma and TNF. Those signals recruited and activated other immune cells within the tumor, including myeloid cells, and helped generate nitric oxide and other molecules capable of killing cancer cells.
🛡️ In other words, the T cells acted almost like an alarm system: they activated the surrounding #immune environment and essentially recruited other cells to help do the killing.
The researchers showed that this tumor clearance could occur even without conventional tumor-specific T-cell recognition, challenging the idea that an effective T-cell response always requires T cells that directly recognize cancer.
💡 Why does this matter?
Many #tumors contain large numbers of “bystander” T cells that recognize viruses or other antigens rather than the tumor itself. If scientists can learn how to safely activate and harness these cells, they could potentially expand the pool of immune cells available to participate in an antitumor response.
The researchers also identified gene-expression patterns associated with this response that correlated with survival in patients with #melanoma, although much more work is needed to understand how this approach could translate to patients.
It’s another reminder that the immune system may have more than one way to attack cancer, sometimes, T cells may be able to kill by proxy. @Nature @NatureComms @NatureMedicine @Masopust_Vezys @oliviacs_ @UMNMSTP @Noah_V_Gavil @snguyen268 @shaleklab @umnmedschool @CFI_UMN @broadinstitute @ragoninstitute
📄 Read the study: https://t.co/ZmphgSm3FP
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Mohammad Fallahi-Sichani @MFallahiSichani
Happy to share our lab's paper published in @CellReports: led by talented PhD student, Yonatan Degefu at @UVABME, showing how cell state #plasticity (in #melanoma) is shaped by co-regulated, competitive, configurable interactions within the AP-1 network: https://t.co/zkJvdIockw
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Elad Sharon @EladSharonMD
RT @ACIR_org: Groeneveldt et al. investigated mechanisms driving early-stage immune-related adverse events (irAEs) in patients with metastatic melanoma treated with combination ICB (anti-PD-1 and anti-CTLA-4). Proteomic analysis of serum identified an early, significant increase of p40, a subunit of IL-12/I-23, prior to the onset of clinically apparent irAEs, which was not associated with ICB efficacy. In mouse models that mimic irAEs in patients, p40 neutralization prevented ICB-induced toxicity, without compromising antitumor T cell immunity, including the establishment of tumor-specific responses, suggesting distinct mechanisms that can be uncoupled. https://t.co/V01wK8kCpI
@CIR_AACR
@ErasmusOncology
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Stephen V Liu, MD @StephenVLiu
RT @LungSummit: @StephenVLiu, at the @etop_ibcsg workshop on T-cell engagers: rational design gives us agents that do exactly what we intended, and toxicities nobody has a routine for yet. The statement borrows that routine from haematology and uveal melanoma, where they were met first.
The position statement from that workshop is out now: https://t.co/feeEZBT5RW
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Immune Regulation News @Immune_News
UV radiation drives high mutational burdens, yet precursor melanocytes accumulate these mutations without triggering immune clearance. @harvardmed researchers looked at the mechanisms behind early immune evasion during #melanoma development.
@ImmunityCP: https://t.co/vaH8ewlYx9 https://t.co/VfUi8YVdd6
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OncLive.com @OncLive
🔬"The fact that we have patients out 5 years corroborates that this could have a big impact for this disease," said Udai S. Kammula, MD, FACS, of @UPMCHillmanCC on TIL therapy outcomes, the UMIS biomarker, and treatment implications in metastatic uveal melanoma.
Read more here 🤔: https://t.co/bwM8WzSEsb
#melsm #oncology
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Elad Sharon @EladSharonMD
RT @OncnephBoston26: Lifileucel has shown activity in PD-1 refractory melanoma, with an ORR of 31.4% and median OS of 13.9 months in the data presented. Five-year data showed a median duration of response of 36.5 months. https://t.co/vyzFQjI2rG
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OncLive.com @OncLive
🌟 This week's #OncFive 🌟:
🫁 @FDA cleared taletrectinib sNDA with new DOR data
🎗️ FDA approves Imlunestrant + abemaciclib in ESR1-mutated advanced or metastatic breast cancer
☀️ Aminolevulinic acid hydrochloride plus PDT FDA approved in basal cell carcinoma
🚫 Accelerated approval for adagrasib plus cetuximab removed in mCRC
🟡 Lutetium Lu 177 dotatate injection approved for GEP-NETs
Learn more 🔗: https://t.co/EHjpN8Gyg2
#lcsm #bcsm #melsm #crcsm #oncology
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OncLive.com @OncLive
🤔 "Some translational work in a small subset of these patients found that those T cells were targeting the neoantigens expressed in [intismeran autogene], linking the drug’s mechanism with the improvement in recurrence-free survival," said Matteo S. Carlino, MBBS, PhD, FRACP, of @Sydney_Uni on how neoantigen-specific T cells link to intismeran autogene’s KEYNOTE-942 recurrence benefit.
Watch here ➡️: https://t.co/lWYWtjsgKR
#melsm #oncology
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Arc Nouvel @ArcNouvel
A cancer vaccine for #melanoma?
The Phase III #INTerpath-001 trial of the individualized mRNA-based therapy intismeran autogene (V940/mRNA-4157) + #pembrolizumab has met its primary recurrence-free survival endpoint and a key secondary endpoint of distant metastasis-free survival.
Arc Nouvel Founder and CEO Dr. Nageatte Ibrahim, who previously worked on this program at @Merck in collaboration with Moderna, explains what this “vaccine” actually is, how it is tailored to an individual patient’s tumor, and what could come next.
Watch the interview below.
#CancerVaccine #mRNA #Immunotherapy #PrecisionOncology #CancerResearch #ClinicalTrials #Oncology #PersonalizedMedicine
[Quoting @HonorHealth: Wait... there's a melanoma vaccine? Dr. Nageatte Ibrahim, clinical investigator at HonorHealth Research Institute, explains. https://t.co/bnBiixD4Fg]
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🧪 Newly Recruiting Trials
1 trial (1 phase III) opened this week, testing darovasertib plus crizotinib
Phase 3 · IDEAYA Biosciences · darovasertib plus crizotinib · Arizona, California, Massachusetts, Michigan, New York, North Carolina +4 more · CT.gov ↗
Agent descriptions from the NCI Thesaurus.
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