Oncolytic virus in gliomas: a review of human clinical investigations.

Gliomas remain one of the more frustrating targets for oncologic therapy. Glioma resistance to conventional therapeutics is a product of their immune-privileged milieu behind the blood-brain barrier, in addition to their suppressive effect on the immune response itself. Taking the lead from the growing success of immunotherapy for systemic cancers, such as lung cancer and melanoma, immunotherapeutics has emerged as a major player in the potential treatment of gliomas, with oncolytic viruses in particular showing significant promise as evidenced by the recent Breakthrough and Fast Tract Designations for PVSRIPO and DNX2401. This review serves as a useful and updated compendium of the completed human clinical investigations for several oncolytic viruses in the treatment of gliomas.

Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas.

PURPOSE: Preclinical animal experiments support the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor (IGF-IR/AS ODN) as an effective potential antitumor agent. We performed a human pilot safety and feasibility study using an IGF-IR/AS ODN strategy in patients with malignant astrocytoma. PATIENTS AND METHODS: Autologous glioma cells collected at surgery were treated ex vivo with an IGF-IR/AS ODN, encapsulated in diffusion chambers, reimplanted in the rectus sheath within 24 hours of craniotomy, and retrieved after a 24-hour in situ incubation. Serial posttreatment assessments included clinical examination, laboratory studies, and magnetic resonance imaging scans. RESULTS: Other than deep venous thrombosis noted in some patients, no other treatment-related side effects were observed. IGF-IR/AS ODN-treated cells, when retrieved and assessed, were < or = 2% intact by trypan blue exclusion, and none of the intact cells were viable in culture thereafter. Parallel Western blots disclosed IGF-IR downregulation to < or = 10% after ex vivo antisense treatment. At follow-up, clinical and radiographic improvements were observed in eight of 12 patients, including three cases of distal recurrence with unexpected spontaneous or postsurgical regression at either the primary or the distant intracranial site. CONCLUSION: Ex vivo IGF-IR/AS ODN treatment of autologous glioma cells induces apoptosis and a host response in vivo without unusual side effects. Subsequent transient and sustained radiographic and clinical improvements warrant further clinical investigations.

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine.

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.

Delayed cortical blindness and recurrent quadriplegia after cervical trauma.

In a retrospective, single-patient case report, we report on a 56-year-old woman with delayed cortical blindness and recurrent quadriplegia after a comminuted C1 burst fracture and a type II odontoid fracture. The vertebral artery is susceptible to injury during trauma to the cervical spine. The resulting vascular compromise may be responsible for a variety of neurologic outcomes. The patient was followed up through personal examination and chart review from initial presentation to 6 months after the injury. Three months after cervical fusion and anticoagulation therapy, the patient was noted to have marked improvement of her visual acuity with almost complete return of strength, as well as normalization of vertebral vessel size. Because of the proximity of the vertebral artery to the atlantoaxial complex, it is susceptible to injury during trauma to the cervical spine. Injury to the vasculature supplying the brain may result in both immediate and delayed neurologic consequences.

Regression of C6 rat brain tumors by cells expressing an antisense insulin-like growth factor I receptor RNA.

We have previously shown that C6 cells expressing an antisense insulin-like growth factor I receptor (IGF-IR) RNA are no longer tumorigenic in syngeneic rats, protecting them from subsequent subcutaneous tumor challenge and causing regression of established subcutaneous tumors. In the present study, we have investigated the efficacy of this strategy on intracerebrally implanted C6 rat glioblastoma cells. We demonstrate that C6 cells expressing an antisense IGF-IR RNA implanted for 24 h in the subcutaneous tissue of the rats are able to elicit an anti-tumor response in the brain, leading to complete brain tumor regression and long-term survival of the rats. These findings suggest the possibility of therapeutic intervention in human gliomas.

Root system regulation of whole plant growth.

New evidence confirms earlier postulates that root signals to shoots, including abscisic acid, nitrate flux, and cytokinins, modify whole plant growth processes including leaf expansion, stomatal behavior, and biosynthesis of photosynthetic enzymes. Root signals are thought to reflect soil water, nutrient, and mechanical attributes, as sensed by roots. Meristematic activities in root tips initiate changes in root architecture, modifying the soil volume subject to root uptake, and may provide multiple sensory and signaling capabilities. Knowledge of root signals regulating whole plant growth processes suggests new analytical and experimental tools for integrated analysis of plant phasic development, optimal growth, and ecological fitness.

Predicting remission in juvenile rheumatoid arthritis with methotrexate treatment.

Forty-nine children with a polyarticular course of juvenile rheumatoid arthritis treated with methotrexate (MTX) for at least one year were analyzed to identify clinical characteristics that would predict remission of arthritis after MTX treatment. Twenty-two children (45%) had remission of arthritis after a mean of 13.6 months of treatment and did not differ from the 27 with persistently active arthritis regarding years of disease before starting MTX, age starting MTX, maximum MTX dose, disease onset type, presence of radiographic joint destruction, concomitant treatment with hydroxychloroquine, sulfasalazine or prednisone, or presence of rheumatoid factor or antinuclear antibodies. Higher dose MTX, earlier treatment, genetic markers, and a standardized route of therapy may yield important information in future studies.

An adjustable collimator for stereotactic radiosurgery.

Stereotactic radiosurgery utilizing a linear accelerator is now carried out using small non-coplanar beams to produce a high-dose volume that is approximately spherical in shape. It is desirable to shape the high-dose region so that it is similar to the target volume thereby reducing the amount of healthy tissue irradiated by a high dose. An adjustable collimator has been developed that can be employed to control the target volume height and diameter. Based on film dosimetry and measurements made with a small parallel-plate ionization chamber it was determined that the beams produced by the collimator have properties that make them suitable for radiosurgery. The basic dosimetry parameters (output factors and tissue maximum ratios, TMR) needed for patient treatment were evaluated. It was found that the diameter and length of the high-dose region produced by the patient rotation method are related to the light-field size at 100 cm from the x-ray target. A more favourable dose distribution was found for the adjustable collimator as compared to treating the same volume by use of the two-target method.

Metronidazole in the treatment of metastatic brain tumors. Results of a controlled clinical trial.

We measured the effect of the radiation enhancer metronidazole on patients with metastatic brain tumors undergoing radiation therapy (RT) in a randomized controlled study. Metronidazole was given in a dose of 6 g/m2 4 hr before each of the first 3 doses of RT to the whole-brain. A total of 3000 rad was delivered in 6 doses. Patients were followed by serial neurological examinations and CT scans. The metronidazole group did not differ from the control group when measured in terms of survival, clinical improvement or improvement on CT scan, whether measured 2 months or 6 months following treatment. Nausea and vomiting was a significant side effect, preventing about 10% of patients from completing the treatment. Metronidazole appears to have no substantial radiation enhancing effect on metastatic brain tumors.