📬 Melanoma Intelligence Digest — Week 2026-W35

Merck and Moderna reported the first positive phase 3 trial of an individualized neoantigen therapy, INTerpath-001, with intismeran autogene plus pembrolizumab meeting RFS and DMFS endpoints in completely resected stage IIB-IV melanoma (n=1,137), while a Nature in vivo CRISPR screen identified P2RY8 and GNAS as T-cell brakes in solid tumors.

⚡ TL;DR

📄 Publications

🐦 Twitter / 🦋 Bluesky

Phase 3 INTerpath-001 is positive: intismeran autogene plus pembrolizumab meets RFS and DMFS in completely resected stage IIB-IV melanoma — INTerpath-001 met its primary recurrence-free survival endpoint and key secondary distant metastasis-free survival endpoint with statistically significant and clinically meaningful improvements versus pembrolizumab alone in completely resected stage IIB-IV melanoma
Genome-wide in vivo CRISPR screens in Nature identify P2RY8 and GNAS as brakes on human T cells in solid tumors — The paper reports the first genome-wide in vivo screens for genetic modifications to enhance human T cell therapies for solid tumors, published in Nature

Full details below ↓

📄 What's Being Published

Manuscripts:

Immune-cytokine signature predicts survival in patients with advanced melanoma treated with oncolytic adenovirus TILT-123 and chemotherapy and IL-2-free adoptive TIL therapy. — Haybout Lyna et al., J Immunother Cancer

17 patients with checkpoint-inhibitor-resistant metastatic melanoma received up to six intratumoral TILT-123 injections followed by TIL infusion, without lymphodepleting chemotherapy or IL-2 post-conditioning; tumor biopsy analyses revealed early innate immune activation with natural killer-cell expansion and cytotoxic gene upregulation, followed by increased intratumoral T-cell infiltration. Enrichment of CD27+CD28+ memory-precursor CD8+ T cells was associated with favorable clinical outcomes, while elevated monocytic myeloid-derived suppressor cells and angiogenic/inflammatory cytokines were associated with disease progression. Correlative analysis in pooled TILT-123 cohorts identified serum epidermal growth factor as a candidate biomarker for stratifying and monitoring patients.

Clinical bottom line: An oncolytic adenovirus armed with TNFa and IL-2 can deliver intratumoral immune activation and TIL engraftment in checkpoint-refractory melanoma without lymphodepleting chemotherapy or systemic IL-2, and myeloid suppression rather than T-cell dose appears to mark the patients who progress.

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🗂 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).

Phase 3 INTerpath-001 is positive: intismeran autogene plus pembrolizumab meets RFS and DMFS in completely resected stage IIB-IV melanoma

INTerpath-001 (NCT05933577; n=1,137) randomized patients with completely resected stage IIB-IV cutaneous melanoma and no prior systemic therapy to intismeran autogene (mRNA-4157) plus pembrolizumab versus pembrolizumab plus placebo, meeting its primary recurrence-free survival and key secondary distant metastasis-free survival endpoints with statistically significant and clinically meaningful improvements — marking the first positive phase III trial of an individualized neoantigen therapy and of an mRNA-based cancer therapy. The study was stopped for positive results at the first interim analysis with no data yet disclosed; intismeran autogene encodes up to 34 patient-specific neoantigens per individual and is described as the first and only combination regimen to demonstrate a clinically meaningful improvement over pembrolizumab alone, a current standard of care in this setting. Professor Georgina Long served as Principal Investigator for Melanoma Institute Australia's participation, and full results are to be presented at a congress later this year. With hazard ratios, durability, and overall survival unreported, clinicians are debating how broadly to counsel the adjuvant melanoma population toward this regimen, with open questions including whether benefit will hold in patients with residual disease after neoadjuvant immunotherapy — INTerpath-001 enrolled only patients with no prior systemic therapy — and whether patient selection or vaccine generation could be guided by ctDNA.

Discussed by: @StephenVLiu, @OncoAlert, @jasonlukemd, @OncoAlert, @EladSharonMD, @EladSharonMD, @kazuki_nozawa, @OncoAlert, @EladSharonMD, @BalazsHalmosMD, @EladSharonMD, @OncoAlert, @OncoAlert, @HHorinouchi, @MelanomaAus, @YGaritaonaindia, @Latinamd, @AnaArance1, @Melanoma_doctor, @EladSharonMD, @VivekSubbiah, @CureMelanoma

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Genome-wide in vivo CRISPR screens in Nature identify P2RY8 and GNAS as brakes on human T cells in solid tumors

A paper in Nature reports the first genome-wide in vivo screens for genetic modifications to enhance human T cell therapies in solid tumors, identifying two distinct brakes: P2RY8, which appeared to make it harder for T cells to enter tumors, and GNAS, which helped transmit suppressive signals tumors use to shut T cells down. In one melanoma model, all 6 mice treated with GNAS-edited CAR T cells achieved durable tumor clearance, and removing both P2RY8 and GNAS simultaneously appeared to address tumor entry and resistance to suppression at once, with improved tumor control demonstrated across pancreatic, lung, uterine sarcoma, and gastroesophageal models. The central debate for melanoma specialists is whether the next generation of cell therapy products should routinely incorporate GNAS or P2RY8 edits, and which clinical setting justifies testing a double-edited product first.

Discussed by: @EladSharonMD, @PatrickHwuMD

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🔥 Top Ranked Tweets

Vivek Subbiah, MD @VivekSubbiah

⭐️🚨 Moderna and Merck say mRNA cancer vaccine succeeded in late-stage melanoma trial.
⭐️So-called “neoantigen” vaccines have long been seen as having potential as cancer treatments, but this is the first randomized Phase 3 clinical trial aimed at definitively proving their benefit. In this case the personalized vaccine, intismeran, was combined with Merck’s Keytruda in adjuvant melanoma, meaning patients’ disease had been surgically removed @OncoAlert

https://t.co/5em9OgrOdQ via @statnews

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