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

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.

Synthetically engineered IgG1 antibody Fc fragments presenting influenza A virus receptor sialic acid inhibit viral haemagglutination activity, but enhance virus replication in cultured A549 cells

“…5 ). As IFN -α therapy is used in the treatment of certain viruses and cancers (47, 48), including glioblastomas (49), these findings may partly explain our earlier observations on the efficacy of N563A Fc-mutants at controlling immune-mediated demyelination by glial cells (32).…”

“…As IFN-a therapy is used in the treatment of certain viruses and cancers (47,48), including glioblastomas (49), these findings may partly explain our earlier observations on the efficacy of N563A Fc-mutants at controlling immune-mediated demyelination by glial cells (32). These data provide a basis for the continued preclinical evaluation of the variably glycosylated Fc in order to support their advancement to clinical studies of viral and/or neurological diseases.…”

Targeting Cellular Components of the Tumor Microenvironment in Solid Malignancies

“…In addition to this, species-specific differences have been demonstrated among murine and human macrophages, further explaining the meager clinical trial results obtained so far despite promising pre-clinical attempts [ 148 ]. Concurrently, on the one hand, myeloid-depleting strategies have so far found a role in TGCT with paxidartinib, on the other hand, myeloid-reprogramming strategies are currently also being explored to promote long-lasting and effective anti-tumor immune responses (NCT03866109) [ 149 , 150 ], or to provide novel effector functions, such as for chimeric antigen receptors-macrophages (NCT04660929) [ 151 ]. Ultimately, CAF targeting is still a largely unexplored area of clinical investigation, due to its great heterogeneity, less characterized functional adaptations, and the scarcity of specific, druggable, targets.…”

Therapeutic utility of engineered myeloid cells in the tumor microenvironment

“…The treatment was well tolerated and the engineered myeloid cells were detected in the bone marrow and peripheral blood up to 14 days post engraftment [32]. In addition, the team that developed the Tie2-monocyte model for cancer therapy [26][27][28]32], recently tested the effect of myeloid cells engineered for the inducible release of IFNα and Interleukin-12 (IL12) in glioblastoma (GBM) [33]. In summary, they generated gene fusions of IFNα and IL12 with destabilizing domains (DDs).…”