MedicalResearch: The poliovirus receptor (CD155) is an onco-fetal cell adhesion
molecule with widespread expression in all solid tumors and particularly
in primary CNS tumors (adult and pediatric). Recombinant nonpathogenic polio–rhinovirus chimera (PVSRIPO) was
generated by replacing a critical piece of the genetic information from
the Sabin type 1 polio vaccine, making PVSRIPO incapable of harming or
killing normal brain cells, but toxic/lethal in cancer cells. In
preclinical models, it has been demonstrated that the infection of tumor
cells, leads to the release of danger signals, which triggers a
recruitment of dendritic/CD4/CD8 T cells and a destruction of tumor
cells by anti-tumor T cells.
The manuscript reports the results of the phase 1 trial of PVSRSIPO
in recurrent WHO grade IV malignant glioma patients. Adult patients with
recurrence of a single glioblastoma lesion, 1-5.5cm in dimension, in a
non-eloquent area of the brain, were enrolled on study. PVSRIPO is
injected slowly over 6.5 hours directly into the tumor via a small
catheter inserted via a small bur hole. Once intratumoral injection is
completed, the catheter is removed and patients are observed for
localized tumor inflammation, followed by tumor contraction. A total of
61 patients were treated on study, 9 patients in a dose escalation phase
and 52 in a dose expansion phase. Side effects observed were in
relation to the localized inflammation of the tumor and depending on the
cerebral functions in close proximity to the tumor: headaches, visual
field changes, hemiparesis, etc.
One patient experienced a brain hemorrhage at the time of catheter
removal, which triggered right sided weakness and aphasia. The patient
remained alive 57.5 months after PVSRIPO infusion at data cutoff of
March 20th, 2018. Two on-study death were observed, a patient
died from cerebral edema and seizures, which was later found to be due
to tumor progression, and one patient died from the complications of an
intracranial hemorrhage while receiving anticoagulation and bevacizumab.
The median overall survival among all 61 patients who received
PVSRIPO was 12.5 months (95% CI, 9.9 to 15.2), comparatively to 11.3
months (95% CI, 9.8 to 12.5) in a historical control group of patients
treated at Duke and who would have met eligibility on trial, would have
the trial been available to them.
At 24 months, the survival plateaued in patients treated with PVSRIPO
with an overall survival rate of 21% (95% CI, 11 to 33) at 24 months
and 36 months in PVSRIPO treated patients, while overall survival in the
historical control group continued to decline, with an overall survival
rates of 14% (95% CI, 8 to 21) at 24 months and 4% (95% CI, 1 to 9) at
36 months in the historical control group.
MedicalResearch.com: What should readers take away from your report?
Response: A total of 61 patients were
treated on the phase 1 trial. No evidence of viral neuropathogenicity or
virus shedding was observed. At data cut-off of March 20, 2018, the
survival rate at 24 months and 36 months was 21% (95% CI, 11 to 33),
with patients remaining alive more than 70 months, more than 69 months,
and more than 57 months after the PVSRIPO infusion. A phase 2 trial is
ongoing, and a trial was initiated in pediatric brain tumor patients and
soon, trials will open for breast and melanoma patients.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: The side effect profile triggered
by immunotherapies require us to take our time, find the right dose and
learn how to help patients in managing/tolerating the side effects from
the treatment, as once the immune response has attacked the tumor, a
number of patients can become long term survivors.
MedicalResearch.com: Is there anything else you would like to add?
Response: Patents for PVSRIPO have been
licensed from Duke University to the start-up company, Istari Oncology.
Seven of the authors now own equity in Istari Oncology. Before these
commercial arrangements were in place, the study had been approved by
the institutional review board at Duke University. Because of conflict
of interest and intellectual property considerations, an external data
and safety monitoring board oversaw the conduct of the study.
Citation: Recurrent Glioblastoma Treated with Recombinant Poliovirus
Annick Desjardins, M.D., Matthias Gromeier, M.D., James E. Herndon,
II, Ph.D., Nike Beaubier, M.D., Dani P. Bolognesi, Ph.D., Allan H.
Friedman, M.D., Henry S. Friedman, M.D., Frances McSherry, M.A., Andrea
M. Muscat, B.Sc., Smita Nair, Ph.D., Katherine B. Peters, M.D.,
Ph.D., Dina Randazzo, D.O., John H. Sampson, M.D., Ph.D., Gordana
Vlahovic, M.D., William T. Harrison,Bigner, M.D., Ph.D.
NEJM June 26, 2018
DOI: 10.1056/NEJMoa1716435