TY  - JOUR
AU  - Birocchi, Filippo
AU  - Cusimano, Melania
AU  - Rossari, Federico
AU  - Beretta, Stefano
AU  - Rancoita, Paola M V
AU  - Ranghetti, Anna
AU  - Colombo, Stefano
AU  - Costa, Barbara Maria
AU  - Angel, Peter
AU  - Sanvito, Francesca
AU  - Callea, Marcella
AU  - Norata, Rossana
AU  - Chaabane, Linda
AU  - Canu, Tamara
AU  - Spinelli, Antonello
AU  - Genua, Marco
AU  - Ostuni, Renato
AU  - Merelli, Ivan
AU  - Coltella, Nadia
AU  - Naldini, Luigi
TI  - Targeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models.
JO  - Science translational medicine
VL  - 14
IS  - 653
SN  - 1946-6234
CY  - Washington, DC
PB  - AAAS
M1  - DKFZ-2022-01518
SP  - eabl4106
PY  - 2022
N1  - DKFZ-ZMBH Alliance
AB  - Glioblastoma multiforme (GBM) is the most common and lethal brain tumor characterized by a strongly immunosuppressive tumor microenvironment (TME) that represents a barrier also for the development of effective immunotherapies. The possibility to revert this hostile TME by immunoactivating cytokines is hampered by the severe toxicity associated with their systemic administration. Here, we exploited a lentiviral vector-based platform to engineer hematopoietic stem cells ex vivo with the aim of releasing, via their tumor-infiltrating monocyte/macrophage progeny, interferon-α (IFN-α) or interleukin-12 (IL-12) at the tumor site with spatial and temporal selectivity. Taking advantage of a syngeneic GBM mouse model, we showed that inducible release of IFN-α within the TME achieved robust tumor inhibition up to eradication and outperformed systemic treatment with the recombinant protein in terms of efficacy, tolerability, and specificity. Single-cell RNA sequencing of the tumor immune infiltrate revealed reprogramming of the immune microenvironment toward a proinflammatory and antitumoral state associated with loss of a macrophage subpopulation shown to be associated with poor prognosis in human GBM. The spatial and temporal control of IL-12 release was critical to overcome an otherwise lethal hematopoietic toxicity while allowing to fully exploit its antitumor activity. Overall, our findings demonstrate a potential therapeutic approach for GBM and set the bases for a recently launched first-in-human clinical trial in patients with GBM.
LB  - PUB:(DE-HGF)16
C6  - pmid:35857642
DO  - DOI:10.1126/scitranslmed.abl4106
UR  - https://inrepo02.dkfz.de/record/180727
ER  -