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Poliovirus shows promise for treatment of advanced glioma
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An intratumoral infusion of recombinant nonpathogenic polio-rhinovirus chimera appeared safe and prolonged survival among patients with stage IV malignant glioma, according to phase 1 study results published in The New England Journal of Medicine.
Survival rate among patients with WHO stage IV malignant glioma is less than 20 months, despite aggressive therapy.
Previous studies have focused on the advancement of various therapies, chemotherapy and targeted agents. However, improvement in survival has remained inconsistent.
Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO) — a live attenuated poliovirus type 1 (Sabin) vaccine — has the ability to recognize poliovirus receptor CD155, which is expressed in neoplastic cells of solid tumors and throughout the tumor microenvironment.
Studies have shown PVSRIPO can create infection among antigen-presenting cells in vitro and activate antigen-presenting cells and allow for T-cell stimulation in preclinical in-vitro assays.
Darell D. Bigner, MD, PhD, professor of pathology at Duke University School of Medicine and director of Preston Robert Tisch Brain Tumor Center at Duke University Medical Center, and colleagues evaluated the toxicity profile of PVSRIPO and compared OS among a group of patients with WHO stage IV glioma vs. a historical control group.
Researchers evaluated seven doses of PVSRIPO among 61 consecutive adults with recurrent supratentorial WHO grade IV malignant glioma with tumors between 1 cm and 5.5 cm in dimension.
Researchers administered an infusion of PVSRIPO via convection-enhanced delivery over 6.5 hours — at a rate of 500 µl per hour — via Medfusion 3500 or 3010 infusion pump (Smiths Medical ASD) and infusion catheter and infusion tubing with PIT400 (Sophysa).
Doses ranged from 107 to 1010 50% tissue-culture infectious doses (TCID50) and started in a dose-escalation phase then developed into a dose-expansion phase.
During dose-escalation, one patient each received dose level 1 (108 TCID50), dose level 2 (3.3 x 108 TCID50) and dose level 3 (109 TCID50); two patients received dose level 4 (3.3 x 109 TCID50) and four patients received dose level 5 (1010 TCID50). During dose expansion, six patients received dose level 2, which was gradually reduced to dose level –1 (5 x 107 TCID50) for 31 patients and to dose level –2 (107 TCID50) for 15 patients.
Researchers identified dose level –1 as the phase 2 dose.
Researchers compared patients who received PVSRIPO with 104 historical controls. Although a similar proportion of patients in the PVSRIPO-treated group (41%) and historical control group (38%) were women, the groups differed in regard to resection at diagnosis and previous treatment failure with bevacizumab (Avastin, Genentech).
The median follow-up of PVSRIPO-treated patients was 27.6 months (95 %CI, 20.5-41.1)
Overall, researchers observed one dose-limiting toxic effect; a patient who received dose level 5 experienced grade 4 hemorrhage after a catheter was removed. Therefore, dose level 5 was reduced to the phase 2 dose.
Among all patients who received PVSRIPO, 69% had grade 1 or grade 2 adverse events attributed to treatment as their most severe event. Nineteen percent of patients in the dose expansion phase had a treatment-related adverse event of grade 3 or higher.
A majority of patients effected by adverse events in the dose expansion phase experienced headache (52%), followed by pyramidal tract syndrome (50%), seizure (45%), dysphasia (28%) and cognitive disturbance (25%).
The median OS among all patients who received PVSRIPO was 12.5 months (95% CI, 9.9-15.2) compared with 11.3 months (95% CI, 9.8-12.5) among historical controls. OS among patients who received PVSRIPO reached a plateau of 21% (95% CI, 11-33) at 24 months, which appeared sustained at 36 months, compared with a historical rate of 4%.
As of March 2018, eight patients had durable radiographic response of treated tumor. Of these, two had complete response and remained alive at more than 70.4 months and more than 15.1 months after PVSRIPO infusion. Three of the eight patients had stable to partial radiographic responses for 60 months, 34 months and 26 months each.
Many questions and problems remain regarding viral approaches to cancer treatment, Dan L. Longo, MD, professor of medicine at Harvard Medical School and hematologist at Dana-Farber Cancer Institute, and Lindsey R. Baden, MD, director of clinical research in the division of infectious diseases at Brigham and Women’s Hospital, as well as the director of infectious diseases at Dana-Farber Cancer Institute, wrote in a related editorial.
“How will local administration interact with systemic immunity such that lesions that are remote
from the injection site will be recognized and eliminated?” they wrote. “How will the presence or absence of pretreatment immunity to the virus affect the efficacy? Will it be possible to overcome pre-existing antiviral immunity, uncertain targeting of the virus to the desired cells, tumor heterogeneity, and possible in-vivo genetic changes in the virus and the tumor such that systemic administration is both possible and effective? Are there dangers from the restoration of viral pathogenicity or replication competence in vivo?
“Stimulating am immune response is inexact; how does one control a destructive overresponse when the stimulus is persistent?” they added. “Much more needs to be learned, but the clinical results to date encourage further exploration of this new treatment approach.” – by Melinda Stevens
Disclosures: Please see the study for a list of all author’s relevant financial disclosures. Longo and Baden report employment with The New England Journal of Medicine as deputy editors, and they are involved in HIV vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network, International AIDS Vaccine Initiative, Crucell/Janssen, Military HIV Research Program, Gates Foundation and the Ragon Institute. Baden also reports grant support from the Ragon Institute, NIH/NIAID and Gates Foundation outside the submitted work.
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