Targeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models

• DOI: 10.1126/scitranslmed.abl4106
• Publication Date: 2022-07-13T17:56:26Z
• Authors: Filippo Birocchi; Melania Cusimano; Federico Rossari; Stefano Beretta; Paola M. V. Rancoita; Anna Ranghetti; Stefano Colombo; Barbara Costa; Peter Angel; Francesca Sanvito; Marcella Callea; Rossana Norata; Linda Chaabane; Tamara Canu; Antonello Spinelli; Marco Genua; Renato Ostuni; Ivan Merelli; Nadia Coltella; Luigi Naldini
• Keywords: Proinflammatory cytokine; Ex vivo

Glioblastoma multiforme (GBM) is the most common and lethal brain tumor characterized by a strongly immunosuppressive microenvironment (TME) that represents barrier also for development of effective immunotherapies. The possibility to revert this hostile TME immunoactivating cytokines hampered severe toxicity associated with their systemic administration. Here, we exploited lentiviral vector–based platform engineer hematopoietic stem cells ex vivo aim releasing, via tumor-infiltrating monocyte/macrophage progeny, interferon-α (IFN-α) or interleukin-12 (IL-12) at site spatial temporal selectivity. Taking advantage syngeneic GBM mouse model, showed inducible release IFN-α within achieved robust inhibition up eradication outperformed treatment recombinant protein in terms efficacy, tolerability, specificity. Single-cell RNA sequencing immune infiltrate revealed reprogramming toward proinflammatory antitumoral state loss macrophage subpopulation shown be poor prognosis human GBM. control IL-12 was critical overcome an otherwise while allowing fully exploit its antitumor activity. Overall, our findings demonstrate potential therapeutic approach set bases recently launched first-in-human clinical trial patients