Intratumoral Delivery of Interferonγ-Secreting Mesenchymal Stromal Cells Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo

Abstract

Neuroblastoma, the most common extracranial solid tumor in childhood, remains a therapeutic challenge. However, one promising patient treatment strategy is the delivery of anti-tumor therapeutic agents via mesenchymal stromal cell (MSC) therapy. MSCs have been safely used to treat genetic bone diseases such as osteogenesis imperfecta, cardiovascular diseases, autoimmune diseases, and cancer. The pro-inflammatory cytokine interferon-gamma (IFNγ) has been shown to decrease tumor proliferation by altering the tumor microenvironment (TME). Despite this, clinical trials of systemic IFNγ therapy have failed due to the high blood concentration required and associated systemic toxicities. Here, we developed an intra-adrenal model of neuroblastoma, characterized by liver and lung metastases. We then engineered MSCs to deliver IFNγ directly to the TME. In vitro, these MSCs polarized murine macrophages to the M1 phenotype. In vivo, we attained a therapeutically active TME concentration of IFNγ without increased systemic concentration or toxicity. The TME-specific IFNγ reduced tumor growth rate and increased survival in two models of T cell deficient athymic nude mice. Absence of this benefit in NOD SCID gamma (NSG) immunodeficient mouse model indicates a mechanism dependent on the innate immune system. IL-17 and IL-23p19, both uniquely M1 polarization markers, transiently increased in the tumor interstitial fluid. Finally, the MSC vehicle did not promote tumor growth. These findings reveal that MSCs can deliver effective cytokine therapy directly to the tumor while avoiding systemic toxicity. This method transiently induces inflammatory M1 macrophage polarization, which reduces tumor burden in our novel neuroblastoma murine model. Stem Cells 2018;36:915-924.

Systemic oncolytic adenovirus delivered in mesenchymal carrier cells modulate tumor infiltrating immune cells and tumor microenvironment in mice with neuroblastoma

“…Today it is well accepted the immunomodulatory role associated to oncolytic virotherapy through several secondary mechanisms derived from the tumor cell infection itself [6]. In our experience, TME changed towards a more inflamed environment, evidenced by the increase of cytokines like CXCL10 and CCL2 [35,36], and the decrease of immunosuppressive molecules (like FoxP3 and Nos2), and molecules that promote tumor growth and invasiveness (like IL10 and TGFβ) [37][38][39]. Therefore, oncolytic virotherapy with Celyvir could have not only a lytic effect in tumor cells, but could also immunomodulate the TME so other therapies can be administered with a higher chance of achieving a clinical response.…”

Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Results from the phase 1/2 TREAT‐ME‐1 trial

“…Several preclinical studies have demonstrated anti‐tumor efficacy using genetically‐engineered MSCs to home transgenes to tumor stroma . In these studies, the modified gene either encoded for a secreted protein that had either a direct or indirect effects on tumor cells, or a ‘suicide’ gene that encoded for an enzyme that converted a prodrug into cytotoxic metabolites; an approach known as gene‐directed enzyme‐producing therapy (GDEPT) …”

IL7-IL12 Engineered Mesenchymal Stem Cells (MSCs) Improve A CAR T Cell Attack Against Colorectal Cancer Cells

“…We here report on the use of bone marrow derived MSCs engineered with IL7 and IL12 to sustain a CAR T cell attack against colorectal cancer. The concept takes benefit of the unique capacity of MSCs to migrate to and to infiltrate into solid tumors [18] and, upon genetic modification, to produce and deliver transgenic cytokines to the tumor.…”

“…The tumor homing capacity was used to deliver therapeutic products to the tumor site by applying genetically engineered MSCs [11][12][13][14][15][16][17]. In particular, the capacity to actively migrate into the tumor tissue and the ease to engineer the cells by viral vectors makes MSCs attractive for delivering transgenic immune modulators in order to shift the tumor bed from an inhibitory to an immune stimulatory environment [18]. For therapeutic purposes, human MSCs moreover have the advantage that the cells are invisible to allo-recognition which allows using these cells as an allogeneic "off-the-shelf" cell product.…”