In Rats with Glioma, Angiogenesis Inhibitor Plus Antitumor Virus Boosts Activity

COLUMBUS, Ohio, Nov. 27 -- Pretreatment with an angiogenesis inhibitor significantly enhanced the antitumor activity of an oncolytic virus in an experimental model of glioma in rats, investigators here found. Both agents are investigational.A single dose of the antiangiogenic peptide cRGD before virus administration reduced tumor vascular permeability, leukocyte infiltration, and levels of interferon-γ protein, Balveen Kaur, Ph.D., of Ohio State University, and colleagues reported in the December issue of the Journal of the National Cancer Institute.
Action Points
Explain to interested patients that this study with rats with brain cancer found that pretreatment with an investigational angiogenesis inhibitor might improve response to a therapeutic virus, also investigational.
Emphasize that the findings came from a study involving rats and that the therapy is investigational.
Pretreated animals also had a significantly longer median survival compared with animals that received only the virus (P0.001).
"To our knowledge, this is the first study to demonstrate that suppression of host immune responses to oncolytic virus therapy can be achieved with single treatment of an angiostatic agent, resulting in the enhanced efficacy of oncolytic virus therapy of tumors," the authors stated.
Malignant cells interact with the tumor microenvironment to influence the growth and spread of solid tumors, Dr. Kaur and colleagues noted. Consequently, therapies that target either malignant cells or the microenvironment alone have only modest efficacy.
Oncolytic viruses have demonstrated considerable antitumor activity in vitro and in animal models, but clinical evaluation has generated minimal evidence of efficacy. The lack of efficacy might reflect changes in the tumor microenvironment, including tumor vascularity, in response to oncolysis, the authors hypothesized.
Investigators examined changes in vascular hyperpermeability in experimental gliomas treated with the oncolytic virus hrR3. Glioma cells were implanted in immunocompetent rats, which were treated seven days later with hrR3. Some rats received angiostatic cRGD four days before virus administration, and others did not.
In animals that did not receive cRGD, the oncolytic virus increased tumor vascular permeability, host leukocyte infiltration, and intratumoral expression of inflammatory cytokine genes. Pretreatment with the angiostatic agent led to substantial inhibition of the effects observed in the animals that received the virus alone.
Intratumoral levels of interferon-γ protein decreased from 203 μg/mg with the virus alone to 75.6 μg/mg with cRGD pretreatment (P=0.006). Viral titers in tumor tissue increased with cRGD pretreatment, and median survival increased from 17 days with virus alone to 21 days.
"This study provides a paradigm for the treatment of tumors using antiangiogenic agents in combination with oncolytic virus," the authors concluded. "Additional studies will be needed to demonstrate the feasibility of a multimodal treatment approach that combines antiangiogenic agents, radiation, chemotherapeutics, and oncolytic virus therapy to destroy glioma."
The authors noted several limitations of the study. "First, the enhanced efficacy of oncolytic viral therapy by cRGD peptide pretreatment was observed in a rat syngeneic glioma model. It would be interesting to extend these findings to human glioma models in athymic nude mice to establish the generalizability of the effect. Second, the increased viral replication supported by tumors pretreated with cRGD peptide could lead to toxic effects that are associated with increased viral burden."
The authors disclosed no conflicts of interest. The study was funded by the National Brain Tumor Foundation, the National Institutes of Health, and the American Association for Neurological Surgeons/Congress of Neurological Surgeons.
Primary source: Journal of the National Cancer InstituteSource reference: Kurozumi K, et al "Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy" J Natl Cancer Inst 2007; 99: 1768-1781.