Immunologic aspects of viral therapy for glioblastoma and implications for interactions with immunotherapies.

INTRODUCTION: The treatment for glioblastoma (GBM) has remained unchanged for the past decade, with only minimal improvements in patient survival. As a result, novel treatments are needed to combat this devastating disease. Immunotherapies are treatments that stimulate the immune system to attack tumor cells and can be either local or systemically delivered. Viral treatments can lead to direct tumor cell death through their natural lifecycle or through the delivery of a suicide gene, with the potential to generate an anti-tumor immune response, making them interesting candidates for combinatorial treatment with immunotherapy. METHODS: We review the current literature surrounding the interactions between oncolytic viruses and the immune system as well as the use of oncolytic viruses combined with immunotherapies for the treatment of GBM. RESULTS: Viral therapies have exhibited preclinical efficacy as single-agents and are being investigated in that manner in clinical trials. Oncolytic viruses have significant interactions with the immune system, although this can also vary depending on the strain of virus. Combinatorial treatments using both oncolytic viruses and immunotherapies have demonstrated promising preclinical findings. CONCLUSIONS: Studies combining viral and immunotherapeutic treatment modalities have provided exciting results thus far and hold great promise for patients with GBM. Additional studies assessing the clinical efficacy of these treatments as well as improved preclinical modeling systems, safety mechanisms, and the balance between treatment efficacy and immune-mediated viral clearance should be considered.

Pulsed Electromagnetic Fields Accelerate Sensorimotor Recovery Following Experimental Disc Herniation.

STUDY DESIGN: An experimental animal study. OBJECTIVE: The aim of this study was to investigate the effect of pulsed electromagnetic fields (PEMF) on recovery of sensorimotor function in a rodent model of disc herniation (DH). SUMMARY OF BACKGROUND DATA: Radiculopathy associated with DH is mediated by proinflammatory cytokines. Although we have demonstrated the anti-inflammatory effects of PEMF on various tissues, we have not investigated the potential therapeutic effect of PEMF on radiculopathy resulting from DH. METHODS: Nineteen rats were divided into three groups: positive control (PC; left L4 nerve ligation) (n = 6), DH alone (DH; exposure of left L4 dorsal root ganglion [DRG] to harvested nucleus pulposus and DRG displacement) (n = 6), and DH + PEMF (n = 7). Rodents from the DH + PEMF group were exposed to PEMF immediately postoperatively and for 3 hours/day until the end of the study. Sensory function was assessed via paw withdrawal thresholds to non-noxious stimuli preoperatively and 1 and 3 days postoperatively, and every 7 days thereafter until 7 weeks after surgery. Motor function was assessed via DigiGait treadmill analysis preoperatively and weekly starting 7 days following surgery until 7 weeks following surgery. RESULTS: All groups demonstrated marked increases in the left hindlimb response threshold postoperatively. However, 1 week following surgery, there was a significant effect of condition on left hindlimb withdrawal thresholds (one-way analysis of variance: F = 3.82, df = 2, P = 0.044) where a more rapid recovery to baseline threshold was evident for DH + PEMF compared to PC and DH alone. All groups demonstrated gait disturbance postoperatively. However, DH + PEMF rodents were able to regain baseline gait speeds before DH and PC rodents. When comparing gait parameters, DH + PEMF showed consistently less impairment postoperatively suggesting that PEMF treatment was associated with less severe gait disturbance. CONCLUSION: These data demonstrate that PEMF accelerates sensorimotor recovery in a rodent model of DH, suggesting that PEMF may be reasonable to evaluate for the clinical management of patients with herniation-associated radiculopathy.Level of Evidence: N/A.

Pulsed electromagnetic fields reduce acute inflammation in the injured rat-tail intervertebral disc.

Pro-inflammatory cytokines are recognized contributors to intervertebral disc (IVD) degeneration and discogenic pain. We have recently reported the anti-inflammatory effect of pulsed electromagnetic fields (PEMF) on IVD cells in vitro. Whether these potentially therapeutic effects are sufficiently potent to influence disc health in vivo has not been demonstrated. We report here the effect of PEMF on acute inflammation arising from a rat-tail IVD injury model. Disc degeneration was induced by percutaneously stabbing the Co6-7, Co7-8, and Co8-9 levels using a 20-gauge needle. Seventy-two (72) rats were divided into three groups: sham control, needle stab, needle stab+PEMF. Treated rats were exposed to PEMF immediately following surgery and for either 4 or 7 days (4 hr/d). Stab and PEMF effects were evaluated by measuring inflammatory cytokine gene expression (RT-PCR) and protein levels (ELISA assay), anabolic and catabolic gene expression (RT-PCR), and histologic changes. We observed in untreated animals that at day 7 after injury, inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor α, and IL-1ß) were significantly increased at both gene and protein levels (P < .05). Similarly, catabolic factors (MMP [metalloproteinases]-2, MMP-13 and the transcriptional factor NF-kß gene expression) were significantly increased (P < .05). At day 7, PEMF treatment significantly inhibited inflammatory cytokine gene and protein expression induced by needle stab injury (P < .05). At day 4, PEMF downregulated FGF-1 and upregulated MMP-2 compared to the stab-only group. These data demonstrate that previously reported anti-inflammatory effects of PEMF on disc cells carry over to the in vivo situation, suggesting potential therapeutic benefits. Though we observed an inhibitory effect of PEMF on acute inflammatory cytokine expression, a consistent effect was not observed for acute changes in disc histology and anabolic and catabolic factor expression. Therefore, these findings should be further investigated in studies of longer duration following needle-stab injury.