July 30, 1999 Curbing immune system's antiviral response allows anticancer agent to reach, attack brain tumors
BOSTON--Teaming tumor-attacking viruses with an approved chemotherapeutic drug may be more effective than either agent alone for treating multi-site brain cancers, reports a team of Massachusetts General Hospital and Harvard Medical School researchers. The findings may advance efforts to treat difficult brain cancers and may shed light on the blood-tumor-brain barrier mystery.
Antonio Chiocca, Harvard Medical School associate professor of surgery at Massachusetts General Hospital and his collaborators found that the drug cyclophosphamide suppressed the immune system's antiviral response. Inhibiting this response allowed a modified strain of herpes simplex virus to reach the brain tumors, enabling it to attack--and in some cases destroy--the tumors. The study is published in the August Nature Medicine.
"This treatment is more efficient than anything we have done before," says Chiocca, who led the study. "By suppressing the antiviral immune mechanism, we were able to deliver into the brain a virus that selectively killed malignant cells but not normal, healthy cells." The researchers hope that their findings will lead to a brain cancer treatment that involves injecting a tumor-specific virus into the patient's bloodstream in a procedure resembling angiography. The study was conducted in rats implanted with human tumors.
Brain cancer typically is aggressive--it often results in multiple tumors that neither the surgeon, radiation, nor chemotherapy can remove--and is quite deadly. Most people diagnosed with malignant glioma, for example, die within a year.
The idea of using oncolytic, or cancer-killing, viruses dates back almost a century, when researchers injected rabies virus into cervical cancer. It was sidelined by the advent of chemotherapy agents in the 1960s but re-emerged in the 1990s.
Past efforts to develop viral therapies for cancers often failed due to the immune system's antiviral response. Viruses that destroyed cultured tumor cells were ineffective when injected into animal models. Chiocca and his colleagues found that part of this antiviral response in rats was the result of an interaction between complement, a well-known group of enzymes, and IgM, or antibodies that course through the body even in the absence of any particular pathogen. Chiocca says that other factors are probably involved in this response. The researchers discovered that cyclophosphamide, which can prevent the production of antibodies, could suppress this antiviral mechanism. Chiocca's group found that one dose of cyclophosphamide inhibited IgM and complement function and allowed for increased survival of the virus in the tumors. The drug also lowered antiviral activity in human plasma samples.
Though Chiocca cannot predict whether these results could hold up in the clinic, he says the virus's performance in this severe model of brain cancer makes him hopeful. "This is the first time, to my knowledge, that someone has effectively infected three large tumors in a rat brain with this virus through the vasculature and caused all three to shrink," he says. A small percentage of animals even survived long term with the tumors gone--and this in a model in which all untreated rats die within two weeks of having the tumors implanted.
The research was funded in part by the National Institutes of Health.
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