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000180727 1001_ $$00000-0002-5214-233X$$aBirocchi, Filippo$$b0
000180727 245__ $$aTargeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models.
000180727 260__ $$aWashington, DC$$bAAAS$$c2022
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000180727 520__ $$aGlioblastoma 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.
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000180727 7001_ $$aCusimano, Melania$$b1
000180727 7001_ $$00000-0003-4493-6380$$aRossari, Federico$$b2
000180727 7001_ $$00000-0003-4375-004X$$aBeretta, Stefano$$b3
000180727 7001_ $$00000-0001-9345-691X$$aRancoita, Paola M V$$b4
000180727 7001_ $$aRanghetti, Anna$$b5
000180727 7001_ $$aColombo, Stefano$$b6
000180727 7001_ $$0P:(DE-He78)2fe44044f40217387daaf299f2eb7340$$aCosta, Barbara Maria$$b7$$udkfz
000180727 7001_ $$0P:(DE-He78)f4f068e71e0d87bf0ad51e6214ab84e9$$aAngel, Peter$$b8$$udkfz
000180727 7001_ $$00000-0002-4046-8420$$aSanvito, Francesca$$b9
000180727 7001_ $$aCallea, Marcella$$b10
000180727 7001_ $$00000-0003-1367-383X$$aNorata, Rossana$$b11
000180727 7001_ $$00000-0003-2782-9938$$aChaabane, Linda$$b12
000180727 7001_ $$00000-0002-4589-9377$$aCanu, Tamara$$b13
000180727 7001_ $$00000-0001-5762-3426$$aSpinelli, Antonello$$b14
000180727 7001_ $$00000-0002-0764-8163$$aGenua, Marco$$b15
000180727 7001_ $$00000-0003-0460-3426$$aOstuni, Renato$$b16
000180727 7001_ $$00000-0003-3587-3680$$aMerelli, Ivan$$b17
000180727 7001_ $$00000-0002-7633-4766$$aColtella, Nadia$$b18
000180727 7001_ $$00000-0002-7835-527X$$aNaldini, Luigi$$b19
000180727 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.abl4106$$gVol. 14, no. 653, p. eabl4106$$n653$$peabl4106$$tScience translational medicine$$v14$$x1946-6234$$y2022
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