Fully intravenous delivery regimen of oncolytic adenovirus coding for TNFa and IL-2 (TILT-123) in patients with advanced solid cancers

BackgroundThe need for intratumoral administration has been a limiting factor for development and use of oncolytic virus based immunotherapy. Igrelimogene litadenorepvec (Ad5/3-E2F-d24-hTNF-IRES-hIL2; TILT-123) is a chimeric oncolytic adenovirus, with fiber knob from serotype 3, and dual selectivity devices, facilitating systemic delivery via intravenous injection.MethodsA fully intravenous delivery regimen of TILT-123 was studied in 6 patients with advanced solid cancers (NCT04695327). The cancer types included three rectal carcinomas, gastric intestinal type carcinoma, pancreatic ductal adenocarcinoma, and liposarcoma. TILT-123 was administered twice daily (each injection 1x1012 viral particles) on days 1, 3, 8, 10, 22, 43 and 64. The split dose regimen was used to increase bioavailability through effects on hepatic Kupffer cells. The primary endpoint was safety by adverse events and laboratory tests. Secondary endpoints included treatment effects by RECIST1.1 and PET criteria. Correlative studies included analysis of blood and tumor biopsies for presence of virus and treatment induced immunological changes.ResultsAll patients were safely treated with a completely intravenous TILT-123 regimen. The most common adverse events included chills, fever, and transiently decreased lymphocyte count (20%, 13% and 7% of all adverse events, respectively). No liver enzyme elevation was noted by ALT, AST, or ALP. No dose-limiting toxicities were seen. Lymphocytes decreased in peripheral blood, compatible with trafficking to tumors. Of patients evaluable by imaging by data cutoff (26 Apr 2024), disease control was seen in 33% of patients (1/3) with RECIST1.1 and 66% of patients (2/3) with PET-based criteria. Tumor biopsies indicated successful delivery of virus to tumors by qPCR and staining of viral proteins.ConclusionsFully intravenous delivery of TILT-123 was safe, resulting in tumor transduction and immunological effects in metastases. Further studies utilizing this regimen are mandated.Clinical trial identificationNCT04695327.Legal entity responsible for the studyTILT Biotherapeutics Ltd.FundingTILT Biotherapeutics Ltd.DisclosureK. 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. 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.H.A. Clubb: Financial Interests, Personal, Full or part-time Employment, Part-time project manager: TILT Biotherapeutics; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics. D.C.A. Quixabeira: Financial Interests, Institutional, Full or part-time Employment: TILT Biotherapeutics. 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, Merck, Roche, Sanofi, Servier. L. Haybout: Financial Interests, Institutional, Full or part-time Employment: Tilt Biotherapeutics Ltd. C. Kistler, S. Sorsa, J.M. Santos, V. Cervera-Carrascon: Financial Interests, Personal, Full or part-time Employment: TILT Biotherapeutics Ltd; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics Ltd. R. Havunen: Financial Interests, Personal, Full or part-time Employment: TILT Biotherapeutics; Financial Interests, Personal, Other, Options: TILT Biotherapeutics. A. Hemminki: Non-Financial Interests, Institutional, Research Grant: Helsinki University Hospital Research 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 Ltd; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics Ltd, Circio Holdings ASA; Other, Personal, Stocks or ownership: Aeruginosa Oy. All other authors have declared no conflicts of interest.