163P - Effect of split intravenous dosing of oncolytic adenovirus TILT-123 on normal tissue versus tumor macrophages and virus bioavailability in patients with advanced solid tumors

Background

Intratumoral administration of oncolytic viruses is the most commonly used delivery method but limits the broader clinical applicability of this therapy. Igrelimogene litadenorepvec (Ad5/3-E2F-d24-hTNF-IRES-hIL2; TILT-123), is a chimeric oncolytic adenovirus suitable for intravenous delivery due to its capsid modification, enabling partial evasion of neutralizing antibodies and potentially enhancing its clinical utility.

Methods

TILT-123 was evaluated as a fully intravenous regimen in six patients with advanced solid tumors in a cohort of TUNIMO (NCT04695327). Patients received 1x10¹² viral particles of TILT-123 twice daily on days 1, 3, 8, 10, 22, 43, and 64. Splitting the dose aimed to increase TILT-123 bioavailability by modulating macrophage mediated clearance. Analyses of pre- and post-treatment blood, serum and tumors included multiplex immunofluorescence, virus immunohistochemistry (IHC), qPCR, and serum proteomics.

Results

Virus quantification results suggest increased TILT-123 concentration and persistence in blood over time. Successful TILT-123 transduction of post-treatment tumors was evidenced by IHC staining for viral proteins and qPCR analysis. Preliminary analysis of metastatic liver biopsies showed accumulation of cytotoxic lymphocytes and macrophages in tumor nests, while macrophages in normal tissues decreased. Analysis of intratumoral macrophages indicated an increase with the split dose regimen compared to biopsies from patients treated with a single-dose regimen.

Conclusions

A fully intravenous split-dose regimen of TILT-123 resulted in increased viral presence over time, tumor transduction and induced immunological changes in patients with advanced solid tumors. Macrophages in tumors increased but decreased in normal tissues suggesting the utility of the split dose regimen in attenuating anti-adenoviral normal tissue sinks. These findings support the feasibility of split-dose systemic administration of TILT-123 in future clinical trials.

Clinical trial identification

NCT04695327.

Legal entity responsible for the study

TILT Biotherapeutics Ltd.

Funding

TILT Biotherapeutics Ltd.

Disclosure

D.C.A. Quixabeira: Financial Interests, Institutional, Full or part-time Employment: TILT Biotherapeutics. K. Jalkanen: Financial Interests, Personal, Advisory Board: MSD, Ipsen, Roche, BMS, Pfizer, Lilly, Novartis, Bayer; Financial Interests, Personal, Stocks/Shares: Faron Pharmaceuticals; Financial Interests, Institutional, Local PI, Conduct of sponsored clinical trial: Novartis; Financial Interests, Institutional, Local PI, Sponsored clinical trial: Exelixis; Financial Interests, Institutional, Local PI, Several clinical trials: BMS, MSD, Roche; Financial Interests, Institutional, Local PI, clinical trials: Incyte; Financial Interests, Institutional, Local PI, Conduct of clinical trials: Pfizer; Financial Interests, Institutional, Local PI, Conduct of clinical trial: Bayer; Financial Interests, Institutional, Local PI, Conduct sponsored trial: Orion Pharma. J. Clubb: Financial Interests, Personal, Full or part-time Employment: TILT Biotherapeutics; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics. T.V. Alanko: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, AstraZeneca, MSD, Roche, Servier, AstraZeneca, Incyte, Eisai, Nordic Drugs; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Full or part-time Employment: Docrates Cancer Center; Financial Interests, Personal, Stocks/Shares: Docrates Cancer Center; Financial Interests, Institutional, Local PI: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, TILT Biotherapeutics, Incyte, MSD. J.T. Kononen: Financial Interests, Personal, Invited Speaker: Merck, Roche, Incyte, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: Docrates; Financial Interests, Personal, Stocks/Shares: Biopsense; Financial Interests, Institutional, Research Grant: Amgen, Eli Lilly, Roche, Sanofi, Servier. L. Haybout: Financial Interests, Personal, Full or part-time Employment: TILT Biotherapeutics. C. Kistler: Financial Interests, Personal, Full or part-time Employment: TILT Biotherapeutics; Financial Interests, Personal, Stocks/Shares, shareholder S. Sorsa: Financial Interests, Personal, Full or part-time Employment: TILT Biotherapeutics; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics. R. Havunen: Financial Interests, Personal, Full or part-time Employment: TILT Biotherapeutics; Financial Interests, Personal, Other, Options: TILT Biotherapeutics. J. Santos: Financial Interests, Personal, Full or part-time Employment: TILT Biotherapeutics; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics. V. Cervera-Carrascon: Financial Interests, Personal, Full or part-time Employment: TILT Biotherapeutics Ltd; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics Ltd. A. Hemminki: Non-Financial Interests, Institutional, Research Grant: Helsinki University Hospital Funds, Cancer Foundation Finland, Jane and Aatos Erkko Foundation, Red Cross Blood Service, Sigrid Juselius Finland, European Commission; Financial Interests, Personal, Financially compensated role: TILT Biotherapeutics; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics, Circio Holdings ASA; Financial Interests, Personal, Stocks or ownership: Aeruginosa Oy. All other authors have declared no conflicts of interest.