Antiviral humoral immunity as biomarker and effector in oncolytic adenovirus TILT-123 therapy
11 affiliations
- 1Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki Faculty of Medicine, Helsinki, Finland
- 2TILT Biotherapeutics Ltd, Helsinki, Finland
- 3Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- 4Merck & Co Inc, Kenilworth, New Jersey, USA
- 5Docrates Cancer Center, Helsinki, Finland
- 6Department of Clinical Physiology and Nuclear Medicine, Turku University Central Hospital, Turku, Finland
- 7Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
- 8Oncology, Mayo Clinic, Rochester, Minnesota, USA
- 9Department of Oncology, National Center for Cancer Immune Therapy (CCIT DK), Copenhagen University Hospital, Herlev, Denmark
- 10Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland
- 11Department of Urology, Helsinki University Hospital (HUS), Helsinki, Finland
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.
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BibTeX
@article{arias2026antiviral,
title = {{Antiviral humoral immunity as biomarker and effector in oncolytic adenovirus TILT-123 therapy}},
author = {Victor Arias and James H Clubb and Tatiana V Kudling and Elise Jirovec and Santeri Artturi Pakola and Lyna Haybout and Dafne C A Quixabeira and Mirte van der Heijden and Nea Ojala and Susanna Grönberg-Vähä-Koskela and Sini Raatikainen and Michael J Chisamore and Katriina Jalkanen and Tuomo Alanko and Jukka Kemppainen and Maria Hellesuo and Anniina Färkkilä and Matthew Stephen Block and Tine Juul Monberg and Inge Marie Svane and Johanna Mäenpää and Suvi Sorsa and Claudia Kistler and João Manuel dos Santos and Anna Kanerva and Otto Hemminki and Victor Cervera-Carrascon and Akseli Hemminki},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = nov,
doi = {10.1136/jitc-2026-016430},
url = {https://doi.org/10.1136/jitc-2026-016430},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Antiviral humoral immunity as biomarker and effector in oncolytic adenovirus TILT-123 therapy
AU - Victor Arias
AU - James H Clubb
AU - Tatiana V Kudling
AU - Elise Jirovec
AU - Santeri Artturi Pakola
AU - Lyna Haybout
AU - Dafne C A Quixabeira
AU - Mirte van der Heijden
AU - Nea Ojala
AU - Susanna Grönberg-Vähä-Koskela
AU - Sini Raatikainen
AU - Michael J Chisamore
AU - Katriina Jalkanen
AU - Tuomo Alanko
AU - Jukka Kemppainen
AU - Maria Hellesuo
AU - Anniina Färkkilä
AU - Matthew Stephen Block
AU - Tine Juul Monberg
AU - Inge Marie Svane
AU - Johanna Mäenpää
AU - Suvi Sorsa
AU - Claudia Kistler
AU - João Manuel dos Santos
AU - Anna Kanerva
AU - Otto Hemminki
AU - Victor Cervera-Carrascon
AU - Akseli Hemminki
PY - 2026
DA - 2026/11/04
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-016430
UR - https://doi.org/10.1136/jitc-2026-016430
AB - 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.
SN - 2051-1426
ER -