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October 27, 2005


Adenovirus serotypes may boost vaccine effectiveness

Vaccines to prevent infection with Ebola, influenza, SARS-associated coronavirus and human immunodeficiency virus are being developed using recombinant forms of the common adenovirus.

In a study to be published in the Journal of General Virology, Simon Barratt-Boyes, associate professor in the Department of Infectious Diseases and Microbiology, collaborated with other researchers at the Graduate School of Public Health and the School of Medicine to develop and test in monkeys a vaccine against the simian counterpart of HIV, based on an uncommon adenovirus serotype Ad35.

A common problem with adenovirus-based vaccines is pre-existing immunity to the adenovirus serotype 5 (Ad5) commonly used in adenovirus-based vaccines. Immunity reduces the effectiveness of the vaccination.

The researchers showed that Ad35-based vaccines induce robust T cell immunity to simian immunodeficiency virus and can boost immunity generated in response to Ad5-based vaccines.

Their findings support the development of vaccines based on Ad35 and other rare adenovirus serotypes for use in vaccines to protect against human diseases.


Researchers present results

School of Medicine researchers presented findings from several studies at the annual meeting of the American Society for Therapeutic Radiology and Oncology held Oct. 16-20.

***Radiosurgery improves survival for patients with multiple brain tumors

A study of 250 patients with cancer that had spread to the brain found that treating multiple brain tumors with radiosurgery improved survival rates compared to brain radiation therapy alone.

In the study, patients with between four and 18 brain tumors underwent gamma knife radiosurgery, a non-invasive procedure that uses cobalt 60 to destroy tumors.

The radiosurgery treatment was used alone, with whole brain radiation or after the failure of whole brain radiation.

The study also found that the volume of tumors, rather than the number of metastases, was a more significant factor in predicting the length of patients’ survival.

“Typically, only patients with one to three brain metastases are considered candidates for stereotactic radiosurgery,” said Ajay K. Bhatnagar, study co-author and UPMC radiation oncology resident.

“However, based on the results from this study, we conclude that the number of brain metastases should not necessarily preclude patients with multiple lesions from this potentially life-saving treatment option.”

Patients who received radiosurgery survived an average of eight months. Among them, those with the best prognosis for survival, ranked class 1 by the radiation therapy oncology group classification system, survived an average of 18 months, compared to a reported historic average of seven months for whole-brain radiation recipients.

Radiosurgery recipients defined as class 2 survived nine months, compared to an average of seven months for whole-brain radiation recipients. Those in the radiosurgery study with the worst prognosis, defined as class 3, survived an average of three months compared to a historic average of two months for those receiving whole brain radiation.

“In the past, these patients were not considered candidates for radiosurgery. The results of our study indicate that treating four or more brain tumors with radiosurgery is safe and effective and translates into a survival benefit for patients,” said UPMC radiation oncology professor John Flickinger, senior author of the study.

***Reducing IMRT side effects in cancer patients

A study evaluating intensity modulated radiation therapy (IMRT) for head and neck cancer found the severity of side effects was directly related to the volume of the radiation dose patients received.

“Despite major advances in chemotherapy and radiation for the treatment of head and neck cancers, many patients continue to suffer debilitating side effects that greatly impact their quality of life,” said study co-author Dwight E. Heron, UPMC director and associate professor of radiation oncology.

“While these high-energy beams are targeted to the tumor site as precisely as possible, they often inadvertently injure healthy tissue that surrounds the tumor site, limiting the doses of radiation that can be used to effectively destroy cancer cells,” Heron said.

“With this study, we sought to discover whether tightly focused radiation beams, such as those provided by IMRT, would make a difference in the severity of side effects associated with treatment and found a distinct dose-response relationship in the oral cavity of patients treated with IMRT in addition to chemotherapy.”

Unlike standard radiation therapy, IMRT delivers radiation in the form of several hundred small beams that converge on a tumor to give a precise dose of radiation, yet pass through normal tissue without doing significant damage.

The study focused on 70 patients with head and neck cancer who were treated with IMRT and chemotherapy.

Each was evaluated for the severity of oral mucositis, or inflammation, based on the IMRT dosage administered.

Oral mucositis is painful and can affect speech and the ability to swallow. Those with severe cases may require tube feeding.

“We found that if we constrain the dose of IMRT, we reduce the toxic effects of treatment,” said Heron.

“These results are encouraging evidence that head and neck cancer patients can benefit from IMRT at specific doses,” he said.

***MammoSite radiation treatment confirmed safe for breast cancer patients

Researchers from UPMC and the University’s Department of Radiation Oncology found that treating breast cancer with MammoSite brachytherapy resulted in few side effects and was generally well tolerated by patients.

Brachytherapy is used following lumpectomy surgery. A catheter is inserted into the breast; then a tiny balloon is inflated and loaded with radioactive seeds to deliver radiation to tissue surrounding the tumor site. MammoSite is manufactured by Cytyc Corp. of Alpharetta, Ga.

The study evaluated toxicity in 100 patients treated between June 2002 and October 2004 at the University of Pittsburgh Cancer Institute.

“Ours is one of the largest single-institution studies to confirm that it does this safely and with an acceptable level of toxicity,” said assistant professor Sushil Beriwal, medical director of radiation oncology at Magee-Womens Hospital.

Patients were followed between three and 30 months after treatment, with an average follow-up time of one year. They were assessed at one week, one month and at three-month intervals after treatment.

While 14 percent of women had to have the catheter removed for various reasons, 86 percent underwent treatment.

Seven percent experienced balloon rupture and 12 percent had wound infections. No patients had serious skin toxicities from treatment.

Seroma (persistence of the cavity where the lump was removed) occurred in 40 percent of patients and lasted more than six months in 26 percent.

The study also evaluated cosmetic outcome of MammoSite treatment by comparing the physical similarity between the treated breast and the untreated breast.

Fifty-six percent of patients had excellent cosmetic outcomes; 37 percent had good cosmetic outcomes and 7 percent had fair cosmetic outcomes.

“Our findings demonstrate that the toxicities associated with MammoSite were similar to results reported in the MammoSite brachytherapy registry trial,” said Beriwal.

“The complications were acceptable and the cosmetic outcome was comparable to what we might see with standard external beam radiation.”

Follow-up studies are planned to assess the effectiveness and the long-term effects of MammoSite compared with standard external beam radiation therapy and other types of breast brachytherapy.


Gene therapy may protect tissue during lung cancer treatment

An animal study indicates gene therapy helps protect normal tissues from damage during a second administration of radiation therapy for non-small cell lung cancer.

“A major challenge in treating lung tumors with radiation is the toxicity of radiation to healthy tissue,” said School of Medicine professor Joel S. Greenberger. “In previous studies, we demonstrated that gene therapy may protect healthy tissues from damage prior to an initial course of radiation therapy. In this study, we found that gene therapy also can protect the same healthy tissue during re-treatment with radiation.”

A related study shows this therapy could be delivered using an inhalation nebulizer, making the treatment clinically feasible.

Greenberger’s study used mice to test the protective effects of manganese superoxide dismutase plasmid liposome (MnSOD-PL) gene therapy. One group of mice got an injection of MnSOD-PL 24 hours before radiation therapy; a second group got radiation alone. Half of the mice that received the radiation dose survived 180 days, compared to 87.5 percent survival of mice that received the gene therapy prior to the radiation.

Survivors were divided again into two groups and given a second radiation treatment. One group received a MnSOD-PL injection before the additional radiation exposure; the other did not.

The mice that received MnSOD-PL before both courses of radiation had the best survival rate overall — 47.6 percent, compared to a 31.6 percent survival rate for those that received no MnSOD-PL prior to the second radiation treatment.

“Administration of this type of gene therapy appeared to prevent the damaging effects of radiation, even when the radiation was re-administered after six months,” said Greenberger. “Future studies will tell us whether this therapy can improve the quality of life for lung cancer patients and help us more effectively treat lung cancer without the damaging side effects.”


Effects of nanotubes to be studied Valerian E. Kagan, professor and vice chairman of the Department of Environmental and Occupational Health (EOH) and director of the Center for Free Radical and Antioxidant Health in the Graduate School of Public Health, was awarded a $1.47 million grant from the National Institute of Occupational Safety and Health (NIOSH) Centers for Disease Control to study potential toxic effects of carbon nanotubes in the lung.

Nano-materials, including single walled carbon nanotubes (SWCNT), are at the leading edge of the rapidly developing field of nanotechnology. While their unique size-dependent properties make these materials superior and indispensable in many areas of human activity, there is growing concern that they, by virtue of those properties, may pose potential environmental and health risks.

While benefits of nano-technology are widely publicized, the study of the possible negative health effects that could arise from their widespread use in consumer and industrial products is just beginning to emerge.

In addition to his own expertise in redox chemistry and biochemistry, Kagan’s team includes investigators knowledgeable in cell and molecular biology of inflammation, interactions with microbial agents and pulmonary toxicology of nano particles.

It is hoped the study will lead to the development of specific antioxidants or new biotechnological approaches to control inflammatory response to decrease the toxicity of SWCNTs.


Small virus is found to aid gene therapy delivery

Pitt investigators have for the first time used gene therapy to successfully treat heart failure and other degenerative muscle problems in animals that genetically are susceptible to a type of muscular dystrophy that also affects humans.

Reporting in the Oct. 25 edition of the journal Circulation, the authors say that this is the first successful attempt to deliver a therapeutic gene throughout the body.

“Previous attempts at systemic gene therapy for muscle have not been very effective because blood vessel capillaries act much like a mosquito net, blocking the gene drugs from reaching the muscle cells. Fortunately, we found a virus that is just small and sneaky enough to get through this net and deliver the therapeutic gene to both skeletal and cardiac muscle cells,” said lead author Xiao Xiao, associate professor of orthopaedic surgery at the School of Medicine.

The researchers used an adeno-associated virus (AAV) to deliver the corrective gene. AAVs are a class of relatively small viruses that do not cause any known disease.

In earlier studies, Xiao’s team found that direct intramuscular injection of AAV was effective in transferring a gene into muscle cells in a fairly wide area around the injection site. However, for muscular dystrophies where many organs and tissues are affected throughout the body, intramuscular injection is not practical for delivering a corrective gene.

Xiao’s team demonstrated that the AAV-8 virus is particularly efficient at penetrating the capillary barrier, making it a good candidate for whole-body gene delivery. In this study, they tested AAV-8 in an animal model of human muscular dystrophy called limb girdle muscular dystrophy, or LGMD.

In human LGMD, defects in a muscle cell membrane protein known as delta-sarcoglycan lead to severe damage and weakness to muscles, particularly around the hips and shoulders — hence the name “limb girdle”— as well as in the heart. Like humans, hamsters with this particular delta-sarcoglycan gene defect have severe muscle wasting and weakness and significantly shortened lifespans due to cardiac and respiratory failure.

After injecting a very high dose of AAV-8 carrying a normal copy of the delta-sarcoglycan gene intravenously into 10-day-old and adult LGMD hamsters, the researchers found that it had been systemically incorporated into skeletal, diaphragm and cardiac muscle cells in both groups.

More importantly, cardiac and lung muscle cells in both newborn- and adult-treated hamsters were able to express the normal protein almost a year later. There were dramatic biochemical and structural improvements in muscle cells in both groups as well.

This was accompanied by better skeletal and cardiac muscle functions. The newborn-treated hamsters had completely normal hearts, when examined at eight and one-half months after gene therapy. The adult hamsters also showed significant improvements in heart muscle structure.

In contrast, untreated hamsters had severe structural and tissue abnormalities of the heart in addition to secondary symptoms of heart failure such as liver problems, swollen lungs and a severe buildup of fluid in the chest and peritoneal cavities.

The AAV-8-treated hamsters were able to run the same distance as normal hamsters before tiring and for much longer than untreated LGMD hamsters.

And, all of the untreated LGMD animals died of heart failure or other complications of muscular dystrophy around 37 weeks, while all of the AAV-8-treated LGMD hamsters survived beyond the 48-week duration of the study.

“When we began the experiment, we anticipated that the treatment would be effective. However, we never imagined it would be so effective, particularly in protecting against or reversing the damage to the heart caused by this mutation and extending life span,” said Tong Zhu, a research associate in the Department of Orthopaedic Surgery and the first author of the study.

“In fact, if this study holds up in human clinical trials, it may have profound implications for the treatment of heart failure,” he said.

Xiao cautioned that human clinical trials of this therapy face several major challenges. The treatment requires the injection of a large amount of the virus. In addition, up to 40 percent of people have antibodies to human AAVs, which may produce an immune response that could reduce the effectiveness of the treatment.

Xiao said the AAV-8 used in the study was isolated from monkeys, making him optimistic that it could deliver the genes before the human immune system produces antibodies to block it. The researchers also used a muscle-specific promoter in the virus, which Xiao said also should lower the risk of an immune response. No immune response to the human delta-sarcoglycan protein was found in the hamsters.

In addition to Xiao and Zhu, other Pitt authors of this study are: Liqiao Zhou, Zhong Wang, Chunping Qiao, Chunlian Chen and Juan Li, Molecular Therapy Laboratory, Department of Orthopaedic Surgery, and Satsuki Mori and Charles McTiernan, Cardiovascular Institute, all from the School of Medicine.

The study is supported by National Institutes of Health grants and a Natural Science Foundation of China grant to Xiao as well as by a National Institutes of Health grant to McTiernan.


Vaccine researcher to receive ACS grant

Zhaoyang You, an assistant professor in the Department of Dermatology, is among the recipients of 121 American Cancer Society research and training grants totaling more than $51 million. Preliminary studies have shown promising results using a novel targeted vaccine strategy to battle aggressive spontaneous metastatic breast tumors and aggressive melanoma in animal models.

This project will help to optimize tumor vaccine design in future clinical trials for patients who have such tumors and provide new insights into the field of tumor immunotherapy.

Since its inception in 1946, the American Cancer Society’s research and training program has funded about $3 billion in cancer research.

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