2. Academic Validation
  3. Dyslipidemia-associated natural IgM improves oncolytic virus TILT-123 efficacy through antibody-dependent enhancement in solid tumors

Dyslipidemia-associated natural IgM improves oncolytic virus TILT-123 efficacy through antibody-dependent enhancement in solid tumors

  • Mol Ther. 2026 Jan 20:S1525-0016(26)00020-1. doi: 10.1016/j.ymthe.2026.01.019.
James Hugo Armstrong Clubb 1,  Santeri Artturi Pakola 2,  Sakari Joenväärä 3,  Tatiana Viktorovna Kudling 1,  Tiialotta Tohmola 3,  Victor Arias 2,  Elise Jirovec 2,  Mirte van der Heijden 2,  Dafne Carolina Alves Quixabeira 1,  Annukka Pasanen 4,  Lyna Haybout 1,  Nea Ojala 2,  Saru Basnet 2,  Arianna Eleuteri 2,  Julia Davila Ferrero 2,  Stella Hirvenoja 2,  Inge Marie Svane 5,  Johanna Mäenpää 6,  Katriina Jalkanen 7,  Matthew Stephen Block 8,  Tuomo Alanko 6,  Tine Monberg 5,  Sanae Zahraoui 9,  Susanna Grönberg-Vähä-Koskela 10,  Natasha Salmelin 11,  Claudia Kistler 9,  Riikka Havunen 1,  Suvi Sorsa 9,  João Manuel Dos Santos 1,  Victor Cervera-Carrascon 1,  Anna Kanerva 12,  Otto Hemminki 13,  Risto Renkonen 3,  Akseli Hemminki 14
Affiliations

Affiliations

  • 1 Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; TILT Biotherapeutics, 00290 Helsinki, Finland.
  • 2 Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland.
  • 3 Transplantation Laboratory, Faculty of Medicine, University of Helsinki, Helsinki, Finland; HUSLAB, Helsinki University Hospital, 00290 Helsinki, Finland.
  • 4 Department of Pathology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland.
  • 5 National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, 2730 Herlev, Denmark.
  • 6 Docrates Cancer Center, 00180 Helsinki, Finland.
  • 7 Comprehensive Cancer Center, Helsinki University Hospital, 00290 Helsinki, Finland.
  • 8 Mayo Clinic Cancer Center, Rochester, MN 55905, USA.
  • 9 TILT Biotherapeutics, 00290 Helsinki, Finland.
  • 10 Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; Comprehensive Cancer Center, Helsinki University Hospital, 00290 Helsinki, Finland.
  • 11 IRCM, Insitute de Reserche en Cancérologie de Monpellier, INSERM U1194, University Montpellier, Institute Régional du Cancer Montpellier, Montpellier, France.
  • 12 Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland.
  • 13 Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; Department of Urology, Helsinki University Hospital, 00290 Helsinki, Finland.
  • 14 Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland; TILT Biotherapeutics, 00290 Helsinki, Finland; Comprehensive Cancer Center, Helsinki University Hospital, 00290 Helsinki, Finland. Electronic address: [email protected].
PMID: 41566775 DOI: 10.1016/j.ymthe.2026.01.019
Abstract

The oncolytic adenovirus TILT-123 (Ad5/3-E2F-d24-hTNFA-IRES-hIL2, igrelimogene litadenorepvec) has demonstrated favorable safety profiles in phase 1 clinical trials in patients with advanced solid tumors (these trials were registered at ClinicalTrials.gov: NCT04695327, NCT05271318, and NCT04217473). In this study, we analyzed the serum proteome of patients treated with TILT-123 monotherapy using mass spectrometry, focusing on samples collected during the initial intravenous administration phase. Functional and correlative analyses revealed that IGLV8-61-encoded natural immunoglobulin M (IgM) was associated with reduced neutralizing activity and improved clinical outcomes, as assessed by positron emission tomography imaging and overall survival. Single-cell B cell receptor Sequencing enabled profiling of the circulating antibody repertoire and detection of IGLV8-61-expressing clones. Recombinant expression of antibody sequences from a responding patient with a history of hyperlipidemia yielded three pentameric natural IgMs capable of binding both TILT-123 and anionic modified low-density lipoprotein. Further characterization revealed that the IgMs significantly enhanced transduction and promoted cell killing in vitro across multiple cell lines. Blocking studies demonstrated transduction was influenced by Fc Receptors pIgR and FcμR. Cross-trial comparisons indicated dyslipidemia as a common feature among responders. Collectively these findings show that dyslipidemia -associated natural IgM enhances the therapeutic efficacy of TILT-123, via antibody-dependent enhancement. These findings may have broader implications for Other oncolytic viruses, an emerging class of tumor immunotherapies.

Keywords

adenovirus; antibody-dependent enhancement; biomarker; cancer; immunotherapy; lipids; natural immunoglobulin M; oncolytic virotherapy; oxLDL; phase I.

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