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
Journal for ImmunoTherapy of Cancer, 2026
Haybout L., Kudling T., Clubb J., Monberg T., Albieri B., Pakola S., Jirovec E., Arias V., Quixabeira D., Juteau S., Ellebæk E., Donia M., Løvendahl Eefsen R., Borch T., Lorentzen T., Hendel H., Vestergaard C., Khammari A., Kistler C., Westergaard M., Met ?., Sorsa S., Hemminki O., Kanerva A., Cervera-Carrascon V., Dréno B., Svane I., Hemminki A.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology Immunotherapy | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
Background
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: NCT04217473 ) in patients with metastatic melanoma resistant to immune checkpoint inhibitors, without lymphodepleting chemotherapy or IL-2 post-conditioning. This study presents a correlative immunological analysis of the phase I TUNINTIL trial evaluating TILT-123 in combination with TIL therapy.
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.