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Researchers have shown that vaccinating mice with a modified form ofa virus containing proteins from breast cancer cells can kill largebreast cancer tumours and tumours that have spread to the lungs.
Therodent model of cancer used in this study closely resembles a type ofbreast cancer seen in humans called HER2-positive. Although othercancer vaccines have shown activity in the treatment of very smalltumours, their ability to influence large, established tumours, such asmany HER2-positive breast cancers, has proven difficult. The study, ledby researchers at the National Cancer Institute (NCI), part of theNational Institutes of Health, appeared in the March 15, 2008, issue ofCancer Research.
Therapeutic cancer vaccines areintended to disrupt new or existing cancerous growth by stimulating thebody’s immune system so that it recognises the cancer as an invader.These vaccines use certain protein molecules on the surface of cancercells, such as the HER2 receptor protein, as the triggers to initiatean immune response.
The modified virus used as a vaccine inthis study showed activity against ErbB2-positive tumours. The ErbB2gene is known as HER2 in humans, and neu is its counterpart in mice.Approximately 20-25% of breast cancers in women are HER2-positive andtumours overexpressing the HER2 receptor protein are more aggressiveand more likely to recur than tumours that do not overexpress theprotein. Thus, the HER2 receptor protein is an important target.
“Atherapeutic vaccine may offer an advantage over treatments, such asmonoclonal antibodies that target a single site on a cancer cell,because it may induce the production of several different antibodiesthat can target multiple regions on a receptor, making it harder forthe tumour to mutate and escape the effects of therapy,” said Jay ABerzofsky, MD, PhD, of the Vaccine Branch at NCI’s Center for CancerResearch (CCR).
The research team, led by Berzofsky, along withJong Myun Park, PhD, and Masaki Terabe, PhD, of the Vaccine Branch, andJohn Morris, MD, of the Metabolism Branch of the CCR, conducted aseries of experiments studying the effectiveness of a vaccinecontaining a modified form of adenovirus, a type of virus thatprimarily affects the respiratory tract, that expresses portions of neu(Ad-neuECTM) in the treatment of breast cancer in mice. They alsoinvestigated the possible mechanism by which the vaccine induces thedestruction of tumour cells.
To create their breast cancermodel, the team induced tumours by injecting TUBO cells – a mousemammary cancer cell line that highly expresses the neu receptor on itssurface – under the skin in mice. The research team found that when theAd-neuECTM vaccine and TUBO cells were injected at the same time,tumours did not develop. In another experiment, the vaccine wasadministered seven, 10, or 15 days after TUBO cells had been injectedinto mice, and tumours had formed. The researchers observed that thetumours were smaller seven days after vaccination; all the tumours haddisappeared between 25 and 45 days after the mice were vaccinated. Themice remained tumour-free through the end of the study.
Theresearchers also looked at the effects of the vaccine on tumours ofdifferent sizes. They found that although tumours as large as 2 cubiccentimeters continued to grow for seven days after immunisation, thesetumours did begin to regress by 10 days and disappeared about 30 daysafter a single vaccination. In a separate experiment, the researchersobserved that tumours as large as 3.5 cubic centimeters disappearedafter a single dose of Ad-neuECTM. Vaccination, however, was notsufficient to treat tumours larger than 5.5 cubic centimeters. Althoughthese tumours did shrink, they started to regrow two weeks after asingle vaccination.
Metastatic tumours are more difficult totreat than original tumours, so Berzofsky’s team also investigated theefficacy of the Ad-neuECTM vaccine on cancer cells (TUBO) that hadtravelled from the site of injection to the lungs of the mice. Theyfound that the timing of vaccine administration and the number ofmetastatic tumours in the lungs played a role in the effectiveness ofthe vaccine. Mice given the vaccine on the same day as the TUBO cellswere injected did not develop metastases to the lungs. However, whenthe vaccine was administered six days after TUBO cells, metastatictumours did form in the lungs and took more than two weeks to regress.In mice with 25 metastatic tumours in their lungs, the tumoursdisappeared in about 21 days with a single dose of the vaccine, andmice with over 200 metastatic tumours in their lungs became tumour-freewithin 38 days.
Conventional chemotherapy is oftenimmediately active against tumours, while therapeutic vaccines taketime to act. Tumours tend to grow for a while before regressing becauseof the time required for the vaccine to induce an immune response. Oncethe immune response was triggered, the tumours in this study werecontrolled and eradicated within four to five weeks.
The researchers found that in vaccinated mice, the total ErbB2/neu protein receptor levels decreased by 45%.
Itremains to be demonstrated the exact cause of how the TUBO cell isinhibited in this mouse model resembling HER2+ breast cancer. Morestudies in animal models should help clarify the underlying mechanismof this growth inhibition.
“These results show the potentialfor a vaccine that induces antibodies to an overexpressed cell surfacereceptor such as HER2,” Berzofsky said. This study was done in mice andcould progress one day to testing in humans.
