Birocchi et al. engineered hematopoietic stem cells for targeted and inducible release of IFNɑ or IL-12 by their monocyte/macrophage progeny at the tumor site and evaluated their efficacy, tolerability, and specificity. Compared to systemic treatment, inducible IFNɑ/IL-12 expression within the TME spared most of the brain and periphery from cytokine toxicity, but achieved a robust and durable response, up to eradication, in a GBM mouse model. Targeted IFNɑ gene therapy inhibited angiogenesis, decreased T cell exhaustion, and reprogramed TAMs toward a proinflammatory state while suppressing a mouse and human protumoral signature.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. Vita-Salute San Raffaele University, 20132 Milan, Ital
Author Info: (1) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. Vita-Salute San Raffaele University, 20132 Milan, Italy. (2) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (3) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. Vita-Salute San Raffaele University, 20132 Milan, Italy. (4) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. Vita-Salute San Raffaele University, 20132 Milan, Italy. (5) CUSSB-University Center for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University, 20132 Milan, Italy. (6) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (7) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (8) Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (9) Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (10) Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (11) Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (12) GLP Test Facility, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (13) Experimental Imaging Center, Preclinical Imaging Facility, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (14) Experimental Imaging Center, Preclinical Imaging Facility, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (15) Experimental Imaging Center, Preclinical Imaging Facility, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (16) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (17) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. Vita-Salute San Raffaele University, 20132 Milan, Italy. (18) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. National Research Council, Institute for Biomedical Technologies, 20054 Segrate, Italy. (19) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. (20) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. Vita-Salute San Raffaele University, 20132 Milan, Italy.
