An IL-7 fusion protein targeting EDA fibronectin upregulates TCF1 on CD8+ T-cells, preferentially accumulates to neoplastic lesions, and boosts PD-1 blockade

• Published in: Journal for immunotherapy of cancer 2024-08, Vol.12 (8), p.e008504
• Main Authors: Di Nitto, Cesare, Ravazza, Domenico, Gilardoni, Ettore, Look, Thomas, Sun, Miaomiao, Prodi, Eleonora, Moisoiu, Vlad, Pellegrino, Christian, Manz, Markus G., Puca, Emanuele, Weller, Michael, Weiss, Tobias, Neri, Dario, De Luca, Roberto
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bispecific; Biomarkers; Blood & organ donations; CD8-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Clinical trials; Clinical/Translational Cancer Immunotherapy; Cloning; Combined Modality Therapy; Cytokines; Female; Fibronectins - genetics; Fibronectins - metabolism; Genes; Hepatocyte Nuclear Factor 1-alpha - metabolism; Humans; Immune Checkpoint Inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Interleukin-7 - metabolism; Interleukin-7 - pharmacology; Liver cancer; Lung cancer; Lymphocytes; Melanoma; Mice; Monoclonal antibodies; Neoplasms - drug therapy; Neoplasms - immunology; Original Research; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Proteins; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Sarcoma; Skin cancer; Tumors; Up-Regulation
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2023-008504

BackgroundAnti-PD-1 antibodies have revolutionized cancer immunotherapy due to their ability to induce long-lasting complete remissions in a proportion of patients. Current research efforts are attempting to identify biomarkers and suitable combination partners to predict or further improve the activity of immune checkpoint inhibitors. Antibody-cytokine fusions are a class of pharmaceuticals that showed the potential to boost the anticancer properties of other immunotherapies. Extradomain A-fibronectin (EDA-FN), which is expressed in most solid and hematological tumors but is virtually undetectable in healthy adult tissues, is an attractive target for the delivery of cytokine at the site of the disease.MethodsIn this work, we describe the generation and characterization of a novel interleukin-7-based fusion protein targeting EDA-FN termed F8(scDb)-IL7. The product consists of the F8 antibody specific to the alternatively spliced EDA of FN in the single-chain diabody (scDb) format fused to human IL-7.ResultsF8(scDb)-IL7 efficiently stimulates human peripheral blood mononuclear cells in vitro. Moreover, the product significantly increases the expression of T Cell Factor 1 (TCF-1) on CD8+T cells compared with an IL2-fusion protein. TCF-1 has emerged as a pivotal transcription factor that influences the durability and potency of immune responses against tumors. In preclinical cancer models, F8(scDb)-IL7 demonstrates potent single-agent activity and eradicates sarcoma lesions when combined with anti-PD-1.ConclusionsOur results provide the rationale to explore the combination of F8(scDb)-IL7 with anti-PD-1 antibodies for the treatment of patients with cancer.