Antiviral humoral immunity as biomarker and effector in oncolytic adenovirus TILT-123 therapy
Year: 2026
Type: article
Abstract: Background Oncolytic adenoviruses are immunotherapeutic agents that selectively replicate in malignant cells, inducing direct oncolysis, and reshaping the tumor microenvironment. While neutralizing antibodies (nAbs) are known to limit viral vector efficacy, emerging evidence suggests they may also have a role in improving clinical outcomes. This study investigates the kinetics, composition, and functional roles of nAbs, and association with overall survival and response rate in patients treated with TILT-123 (igrelimogene litadenorepvec), an Ad5/3 oncolytic adenovirus encoding tumor necrosis factor and interleukin-2.Methods Multiple serum samples from 58 patients enrolled in three TILT-123 phase I clinical trials ( NCT04695327, NCT04217473, NCT05271318) were analyzed for anti-TILT-123 nAbs using a cell-based functional neutralization assay. ELISA was used to quantify IgM, IgA, and IgG targeting TILT-123. Functional antibody signaling studies included antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis (ADCP) assays. Serum proteomics, peripheral blood mononuclear cell (PBMC) profiling, and tumor immunofluorescence/RNA-seq were used to immunologically contextualize nAb induction. Survival was evaluated by Kaplan-Meier analysis, and responses by RECIST v1.1. Biomarker assessment for clinical benefit was evaluated using confusion matrices.Results Cross-trial analysis demonstrated induction of nAb titers against TILT-123. Patients achieving high neutralizing titers early on-treatment (days 8–22) had longer survival (median OS 280 vs 190 days) and higher response rates. Baseline anti-TILT-123 IgG and IgM levels correlated with prolonged OS. ADCP activity on day 36 was associated with improved survival and disease control. Integrated serum, PBMC, and tumor IF/RNA-seq analyses supported humoral immune remodeling and increased immune trafficking and identified lymphotoxin-α as a systemic driver of early nAb induction. Early on-treatment high nAb titers emerged as the strongest single biomarker of clinical benefit, while combinatorial analyses suggested that incorporating additional factors, such as baseline nAb titers or lymphotoxin-α levels, may enhance biomarker suitability.Conclusions High early on-treatment anti-TILT-123 nAb titers were associated with improved clinical outcomes, while ADCP activity and a pro-humoral systemic milieu supported functional roles beyond viral neutralization. These findings identify nAbs and antiviral humoral immunity as candidate biomarkers and potential effector mechanisms in oncolytic virus therapy development.
Authors: Victor Arias, James H Clubb, Tatiana V Kudling, Elise Jirovec, Santeri Artturi Pakola, Lyna Haybout, Dafne C A Quixabeira, Mirte van der Heijden, Nea Ojala, Susanna Grönberg-Vähä-Koskela, Sini Raatikainen, Michael J Chisamore, Katriina Jalkanen, Tuomo Alanko, Jukka Kemppainen, Maria Hellesuo, Anniina Färkkilä, Matthew Stephen Block, Tine Juul Monberg, Inge Marie Svane, Johanna Mäenpää, Suvi Sorsa, Claudia Kistler, João Manuel dos Santos, Anna Kanerva, Otto Hemminki, Victor Cervera-Carrascon, Akseli Hemminki
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
Award: G2109136156
OpenAlex ID: W7225264755