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
Lyna Haybout, Tatiana V Kudling, James H Clubb, Tine Juul Monberg, Benedetta Albieri, Santeri Artturi Pakola, Elise Jirovec, Victor Arias, Dafne C A Quixabeira, Susanna Juteau, Eva Ellebæk, Marco Donia, Rikke Løvendahl Eefsen, Troels Holz Borch, Torben Lorentzen, Helle Hendel, Cecilie Dam Vestergaard, Amir Khammari, Claudia Kistler, Marie Christine Wulff Westergaard, Özcan Met, Suvi Sorsa, Otto Hemminki, Anna Kanerva, Victor Cervera-Carrascon, Brigitte Dréno, Inge Marie Svane, Akseli HemminkiBackground
Metastatic melanoma resistant to immune checkpoint inhibitors remains difficult to treat, and while adoptive tumor-infiltrating lymphocyte (TIL) therapy has shown durable responses, its reliance on lymphodepleting chemotherapy and high-dose interleukin (IL)-2 causes toxicity that may limit patient eligibility. The dual-cytokine-armed oncolytic adenovirus igrelimogene litadenorepvec (TILT-123) was administered with TILs in the TUNINTIL trial (trial registration:
Methods
The TUNINTIL trial was a first-in-human, open-label, dose-escalation, multicenter, multinational phase I trial. 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. Systemic immune profiling (serum proteomics, flow cytometry, interferon-γ ELISpot assay), intratumoral immune cell–cell profiling (multiplex immunofluorescence, H&E, adenovirus E1a immunohistochemistry), quantitative PCR, and neutralizing antibody responses were assessed at defined time points through the trial, with survival follow-up updated to March 2026. Response criteria were evaluated using Response Evaluation Criteria in Solid Tumors V.1.1 and positron emission tomography-based criteria. Statistical analyses included Kaplan-Meier survival with log-rank tests, Mann-Whitney U tests, Pearson correlation, and receiver operating characteristic/area under the curve analysis for biomarker cut-off determination.
Results
Tumor biopsy analyses revealed an early innate immune activation marked by natural killer-cell expansion and cytotoxic gene upregulation, followed by increased intratumoral T-cell infiltration. This occurred without lymphodepleting chemotherapy or post-conditioning IL-2. Intratumoral viral DNA was detectable in a subset of patients. The enrichment of CD27+CD28+ memory-precursor CD8+ T cell was associated with favorable clinical outcomes. Elevated monocytic myeloid-derived suppressor cells and angiogenic/inflammatory cytokines following combination treatment were associated with disease progression, highlighting the role of immunosuppressive myeloid subsets as potential mediators of therapeutic resistance. Additionally, correlative analysis in pooled TILT-123 cohorts identified serum epidermal growth factor as a candidate biomarker for stratifying and monitoring patients.
Conclusions
These findings provide mechanistic insights into TILT-123 combined with TIL therapy and propose future directions for biomarker-guided clinical studies.
Trial registration number