Intravenous delivery of oncolytic adenovirus TILT-123 results in systemic tumor transduction and accumulation of lymphocytes.

person Dafne Carolina Alves Quixabeira TILT Biotherapeutics Ltd., Helsinki, Finland info_outline Dafne Carolina Alves Quixabeira, Elise Jirovec, James Clubb, Santeri Pakola, Joao Manuel Santos, Katriina Johanna Jalkanen, Tuomo Alanko, Susanna Juteau, Matthew Stephen Block, Johanna Unelma Maenpaa, Daniel A. Adamo, Tine Monberg, Brigitte Dreno, Annabrita Schoonenberg, Eva Ellebaek, Marco Donia, Inge Marie Svane, Suvi Sorsa, Victor Cervera, Akseli Hemminki

Authors person Dafne Carolina Alves Quixabeira TILT Biotherapeutics Ltd., Helsinki, Finland info_outline Dafne Carolina Alves Quixabeira, Elise Jirovec, James Clubb, Santeri Pakola, Joao Manuel Santos, Katriina Johanna Jalkanen, Tuomo Alanko, Susanna Juteau, Matthew Stephen Block, Johanna Unelma Maenpaa, Daniel A. Adamo, Tine Monberg, Brigitte Dreno, Annabrita Schoonenberg, Eva Ellebaek, Marco Donia, Inge Marie Svane, Suvi Sorsa, Victor Cervera, Akseli Hemminki Organizations TILT Biotherapeutics Ltd., Helsinki, Finland, Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland, TILT Biotherapeutics, Helsinki, Finland, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland, Docrates Cancer Center, Helsinki, Finland, Department of Pathology, Helsinki University Hospital, Helsinki, Finland, Mayo Clinic, Rochester, MN, Department of Radiology, Mayo Clinic, Rochester, MN, National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark, Nantes Université, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, Nantes, France, Digital Microscopy and Molecular Pathology Unit, Institute for Molecular Medicine Finland, Helsinki, Finland, National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark, Herlev Hospital, Herlev, Denmark Abstract Disclosures Research Funding TILT Biotherapeutics Ltd. Background: Immune checkpoint inhibitors provide limited benefit in patients with immunologically cold tumors, characterized by a lack of T cells. This creates a niche for T cell-inducing agents such as TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFa-IRES-hIL2). While the 5/3 chimeric oncolytic adenovirus platform prompts potent immunogenic capacity per se , this virus has been armed with TNFa and IL-2 selected based on their ability to activate and attract T cells into tumors. TILT-123 capsid modification, and double selectivity devices for virus replication in cancer cells only, allow intravenous use of TILT-123. This is an important advantage over conventional oncolytic viruses whose widespread use has been hindered by the need for intratumoral injection. Methods: Here we report tumor transduction, pharmacokinetic and immune effects of a single intravenous administration of TILT-123 from three Phase 1 dose escalation clinical trials (TUNIMO-NCT04695327, TUNINTIL-NCT04217473, and PROTA-NCT05271318), with a total of 52 patients. Overall, the most common tumor types were melanoma (20), ovarian cancer (18) and sarcoma (7). In each of these trials, the first TILT-123 injection was performed intravenously, and a tumor biopsy collected 7 days later. Peripheral blood was collected before and after systemic TILT-123 treatment. No other therapy was administered concurrently. Presence of virus in blood was detected with qPCR, while presence of virus in tumor biopsies was measured with immunohistochemistry (IHC) for adenovirus proteins. Immune changes in tumors were evaluated by IHC. Results: TILT-123 was detected in the peripheral blood of all treated patients. Virus concentration was highest at 1 hour after administration, with lower levels seen 16 hours post-injection. Concurrently, IFN-γ levels increased in the patients´ serum. The lowest TILT-123 blood concentrations were observed with the lowest dose, with progressive increases in subsequent cohorts. At higher doses, TILT-123 was detected circulating in blood one week post-administration. Treatment was safe and no dose-limiting toxicity was encountered. Overall, signs of TILT-123 transduction in tumors were observed in 75% of patients evaluated in all three trials, 80% in TUNIMO patients, and 63.64% in TUNINTIL patients. Early results from PROTA suggest a positive effect of TILT-123 in tumors from all cohorts´ dosages studied. Conclusions: In summary, intravenous injection of TILT-123 results in persistence of the virus in peripheral blood for up to 7 days. Tumor transduction was observed in 75% of patients in three Phase I trials on day 8 post TILT-123 systemic administration. These data suggest that TILT-123 could be developed as an intravenous therapy. However, further increases in tumor transduction could be achieved by using multiple intravenous injections of TILT-123. Clinical trial information: NCT04695327 ; NCT04217473 ; NCT05271318 .

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