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

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.