Abstract
Results from a recent phase I clinical trial offer preliminary evidence that a modified poliovirus may improve overall survival in patients with glioblastoma. Some experts note, however, that the therapy needs to be studied in later-stage clinical trials.
A modified poliovirus may improve overall survival in patients with glioblastoma, an aggressive, usually fatal brain cancer, according to preliminary results from a phase I clinical trial (N Engl J Med 2018;379:150–61).
“Poliovirus is very interesting for this cancer-targeting idea because of its receptor,” says Matthias Gromeier, MD, of Duke University in Durham, NC, a lead author of the study. He explains that the virus binds to the surface receptor CD155, which is expressed in cells in the spinal cord, as well as in almost all neoplastic solid-tumor cells and in antigen-presenting cells such as macrophages, dendritic cells, and B cells.
Previously, Gromeier and his team created their modified poliovirus—the recombinant nonpathogenic polio–rhinovirus chimera (PVSRIPO)—by replacing a portion of the poliovirus genome with the corresponding section of the common-cold virus genome. In a 2017 study, they established a possible mechanism for how PVSRIPO fights cancer: It enters CD155-expressing tumor cells and destroys or damages them, prompting a proinflammatory immune response from antigen-presenting cells in the tumor (Sci Transl Med 2017;9:eaan4220). This immune response elicits a sustained antitumor response.
Now, the team is testing PVSRIPO in patients with glioblastoma. “Recurrent glioblastoma is an untreatable cancer—therapies invariably fail,” Gromeier says. Senior author Darell Bigner, MD, also of Duke, adds that virtually all glioblastomas recur after standard-of-care treatment with surgery, radiation, and chemotherapy.
For the phase I trial, researchers infused PVSRIPO into brain tumors in 61 patients with recurrent, grade IV glioblastoma. In a preliminary analysis, patients had a median overall survival of 12.5 months, compared with 11.3 months in 104 matched historical controls. Additionally, 21% of patients were alive at 24 and 36 months, compared with 14% and 4%, respectively, in the controls.
Schematic model of poliovirus binding CD155, with extracellular domain shown in purple.
“What we're excited about is that we can achieve long-term control of recurrent glioblastoma in a subset of patients,” Gromeier says. “That's very promising—this is what we want to build on.” The researchers have initiated a phase II trial of PVSRIPO in glioblastoma and plan to pursue a phase I trial that combines PVSRIPO with an anti–PD-L1 inhibitor. In addition, they plan to launch trials in breast cancer and melanoma this fall.
“I think that it's an interesting study, but we are cautiously optimistic,” says Michael Lim, MD, director of the Johns Hopkins Brain Tumor Immunotherapy program in Baltimore, MD, emphasizing that phase I trials are primarily designed to establish safety and dosing, with efficacy as a secondary measure.
Donald O'Rourke, MD, of the University of Pennsylvania in Philadelphia, agrees that the results are intriguing, “but it's not a finished study.” He says follow-up studies must include a true control group, avoid selection bias, and classify molecular subtypes of glioblastoma. He also thinks more research is needed on the tumor microenvironment to understand the local immune response to PVSRIPO.
However, he notes an increasing interest in oncolytic therapies and precedent for success: In 2015, the FDA approved talimogene laherparepvec (T-VEC/Imlygic; Amgen), a modified herpes virus, for metastatic melanoma.
“The idea of injecting locally into the brain is becoming more and more appealing—there's this growing notion that you'll have a more efficacious effect if you try to induce the immune response locally rather than systemically,” he says. “I think we can learn from what they've done [with PVSRIPO], but we still need much greater examination of which patients responded and why.” –Catherine Caruso
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