👤 Saphala Dhital

Malignant gliomas (MGs) are the most common primary brain malignancies and are considered universally fatal. Oncolytic herpes simplex viruses (oHSVs) are promising immunotherapeutics capable of selectively lysing cancer cells, eliciting antitumor immunity, and providing local delivery of immune-activating transgenes. Interleukin 27 (IL-27) is a pleiotropic cytokine capable of enhancing tumor-reactive cytotoxic T lymphocyte (CTL) function while also possessing neuroprotective properties. We hypothesized that IL-27 expression by oHSV would enhance CTL function and improve antiglioma therapeutic activity. We developed an oHSV that expresses IL-27 (C027). The antiglioma efficacy of C027 was tested in three syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (SB28, KR158) glioma lines. Spectral flow cytometry was used to assess immunophenotypic and functional changes in the tumor infiltrates and systemically. To further investigate the C027-related CTL activity, we employed in vivo cell-specific depletion and IL-27 blockade alongside in vitro T cell stimulation assays. Local and systemic antitumor memory was evaluated by both orthotopic and flank tumor rechallenge of C027-treated long-term survivors. C027 significantly prolonged survival in syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (KR158, SB28) glioma lines. In the CT-2A model, IL-27-expressing oHSV treatment was associated with increased intratumoral multifunctional effector CTLs and functional T cell populations systemically. Mechanistically, both CD8 T cells and IL-27 were required for the C027 survival benefit in vivo and IL-27 enhanced CTL function in vitro. C027-treated mice that survived their initial tumors had local and systemic antiglioma memory rejecting tumors on rechallenge. Our findings demonstrate that IL-27 expression by oHSV significantly improves antiglioma therapeutic efficacy, enhances CTL effector function, and induces durable immune memory. Thus, IL-27-oHSV may provide a promising therapeutic approach for MGs. Show less

Malignant gliomas (MG) are the most common primary brain malignancies and are considered universally fatal. Oncolytic HSVs (oHSV) are promising immunotherapeutics capable of selectively lysing cancer cells, eliciting anti-tumor immunity, and providing local delivery of immune-activating transgenes. IL-27 is a pleiotropic cytokine capable of enhancing tumor-reactive cytotoxic T cell (CTL) function while also possessing neuroprotective properties. We hypothesized that IL-27 expression by oHSV would enhance CTL function and improve anti-glioma therapeutic activity. We developed an oncolytic herpes simplex virus (oHSV) that expresses IL-27 (C027). The anti-glioma efficacy of C027 was tested in three syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (SB28, KR158) glioma lines. Spectral flow cytometry was used to assess immunophenotypic and functional changes in the tumor infiltrates and systemically. To further investigate the C027-related CTL activity, we employed C027 significantly prolonged survival in syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (KR158, SB28) glioma lines. In the CT-2A model, IL-27-expressing oHSV treatment was associated with increased intratumoral multifunctional effector cytotoxic T lymphocytes (CTL) and functional T cell populations systemically. Mechanistically, both CD8 T cells and IL-27 were required for the C027 survival benefit Our findings demonstrate that IL-27 expression by oHSV significantly improves anti-glioma therapeutic efficacy, enhances CTL effector function, and induces durable immune memory. Thus, IL-27-oHSV may provide a promising therapeutic approach for malignant gliomas. Show less

An Abdominal aortic aneurysm (AAA), a deadly disease in elderly population, is featured by expansion of aortic diameter, degradation and weakening of vasculature. Its common and significant characteristics are disarray and inflammation in vasculature. We tested the hypothesis that the reversal of abdominal aortic aneurysm by pentagalloyl glucose-loaded nanoparticles (PGG-NPs) therapy that targets degraded elastin suppresses inflammatory and immune markers to ameliorate the pathophysiology of the disease in advance stage aneurysm in a porcine pancreatic elastase (PPE)-induced mouse model of AAA. After induction of aneurysm in pathogen-free C57BL/6 male mice by applying PPE peri-adventitially to the abdominal aorta, once a week for two doses of intravenous injections of pentagalloyl glucose-loaded nanoparticles (PGG-NPs) conjugated with elastin targeted antibody were used to reverse the aneurysms. We showed that PGG-NPs therapy could suppress infiltration of macrophages, CD8 and CD4 subsets of T cells, matrix metalloproteinases (MMPs), inflammatory cytokines interferon (IFN-γ) and interleukin (IL)-6 at the local and systemic level. Moreover, such PGG-NPs therapy increases the induction of anti-inflammatory cytokines IL-13, IL-27 and IL-10 at the local and systemic level. The therapy also led to remodeling of elastic lamina at the aneurysm site. Nanoparticles-loaded pentagalloyl glucose therapy can be an effective treatment option against advanced stage aneurysms to reverse the disease by ameliorating inflammation and restoring arterial homeostasis. Show less