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Immunotherapy with peptide vaccines may offer a much-needed therapeutic option for gliomas in children, which carry a poor prognosis despite current treatments.
In a pilot trial of subcutaneous vaccinations with peptides for glioma-associated antigen (GAA) epitopes in children who have been newly diagnosed with brain stem gliomas, cerebral high-grade gliomas, or recurrent gliomas, the immunotherapy was well tolerated and demonstrated immunologic and clinical activity, Dr. Ian F. Pollack reported April 2 at the annual meeting of the American Association for Cancer Research.
For the pilot study Dr. Pollack, chief of pediatric neurosurgery at Children’s Hospital of Pittsburgh Brain Care Institute, and his colleagues have enrolled 27 human leukocyte antigen (HLA) A2–positive children to date, including 16 who are newly diagnosed with brain stem gliomas, 5 with newly diagnosed high-grade gliomas, and 6 with recurrent gliomas. The GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13RA2), and survivin, he said.
All of the children received eight courses of subcutaneous vaccinations with peptides for GAA epitopes emulsified in Montanide-ISA-51 every 3 weeks, along with intramuscular injections of the immunoadjuvant poly-ICLC, which promotes the infiltration of effector T cells into intracranial gliomas.
“Our primary end points were safety and T-cell response against vaccine-targeted [GAAs],” he said, noting that treatment response was assessed clinically and by MRI.
The preliminary results reported at the meeting are based on an interim analysis of 22 evaluable patients. To date, no non–central nervous system toxicities have limited the vaccine dosages, Dr. Pollack said. Of the 22 children, 4 showed signs of rapidly progressive disease, 14 had stable disease for more than 3 months, 3 had sustained partial responses, and 1 had prolonged disease-free status after surgery, he reported.
Symptomatic “pseudoprogression” – consisting of transient neurologic deterioration and tumor enlargement, followed by tumor regression and stabilization on decreasing steroid doses with sustained partial response – was observed in four of the children with brain stem glioma, said Dr. Pollack, who is also codirector of the University of Pittsburgh Cancer Institute’s brain tumor program.
Results of the ELISPOT (enzyme-linked immunosorbent spot) assay, which was completed in seven of the children, showed responses in six of them. Specifically, the investigators observed responses to IL-13RA2 in five cases, EphA2 in three cases, and survivin in three cases, Dr. Pollack said.
“Based on what we’ve seen so far, it seems that these kids are able to mount immune responses to the vaccine at high rates, possibly higher than we’ve seen in adult studies,” likely because of their robust immune systems, he said in an interview.
The observation of immunologic and clinical response – particularly the evidence of tumor shrinkage in children with very high-risk tumors – “has been extremely encouraging and somewhat surprising,” Dr. Pollack reported. “This is the first study of its type that examined peptide vaccine therapy for children with brain tumors like this.”
The findings are especially notable because children with these tumors generally do not respond well to standard chemotherapy, he said, stressing that if further study validates the early findings, “immunotherapy may be a promising strategy to control tumor growth.”
The study was funded by the National Institutes of Health. Dr. Pollack disclosed having no potential conflicts of interest.
Source: Elsevier Medical News
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Vaccines for measles were not associated with an increased risk of febrile seizures* among 4-6 year olds during the six weeks after vaccination, according to a study by the Kaiser Permanente Vaccine Study Center that appears in the current issue of Pediatrics.
Funded by the U.S. Centers for Disease Control, the study of 86,750 children follows an earlier study published in Pediatrics that showed one particular combination of measles-containing vaccine - the measles, mumps, rubella and chickenpox containing vaccination (or MMRV) - was associated with an increased risk of febrile seizures in 1-to-2-year-old children, compared with same-day administration of the separate vaccine for MMR (measles, mumps, rubella) and the V (varicella) vaccine for chicken pox. This new study sought to evaluate, for the first time, the risk of febrile seizures following MMRV or separate MMR plus V vaccines among 4-6 year olds and found no increased risk of febrile seizures.
In the United States, children receive two doses of measles, mumps,rubella and varicella vaccines - the first between 1-2 years and the second between ages 4-6. Among 1-2 year olds, the risk of febrile seizures 7-10 days after MMRV was double that of separate MMR+V. For children aged 4-6 receiving their second dose, no such association was found with either measles vaccine combination, according to Kaiser Permanente researchers.
This study of 4-6 year olds analyzed 86,750 children aged 48-83 months old from seven participating Vaccine Safety Datalink sites between January 2000 and October 2008 who received either MMRV; separately administered, same-day MMR plus varicella; or MMR or varicella vaccines alone. The results provide reassuring evidence that neither MMRV, nor MMR plus V, appear to be associated with an increased risk of post-vaccination febrile seizures in this 4-6 age group.
This study builds on the work of a previous study published in Pediatrics in June 2010 that showed that the combination vaccine for measles, mumps, rubella and chickenpox (MMRV) is associated with double the risk of febrile seizures for 1-to-2 year-olds compared with same-day administration of the separate vaccine for measles, mumps, rubella (MMR) and the varicella (V) vaccine for chicken pox.
The Vaccine Safety Datalink project is a collaborative effort among CDC's Immunization Safety Office and eight managed care organizations: Kaiser Permanente Northern California, Kaiser Permanente Southern California, Kaiser Permanente Colorado, Kaiser Permanente Northwest, Health Partners (Minn.), Group Health Cooperative (Wash.), Marshfield Clinic (Wisc.) and Harvard Pilgrim Health Care (Mass.). The VSD project was established in 1990 to monitor immunization safety and address the gaps in scientific knowledge about rare and serious events following immunization. The VSD shares electronic health records from the organizations' health systems.
MMRV was licensed by the FDA in 2005 and subsequently recommended by the Advisory Committee on Immunization Practices in 2006. Although pre-licensure studies of MMRV among 1-2 year olds noted higher rates of fever and measles-like rash one to two weeks post vaccination when compared with separate MMR+V, it was unknown at the time of MMRV's licensure whether a higher rate of fevers was similarly associated with increased risk of febrile seizures. In February 2008, Kaiser Permanente researchers alerted the CDC's Advisory Committee on Immunization Practices to preliminary evidence of an increased risk of febrile seizures following MMRV for 1-2 year olds, findings which were subsequently confirmed in the 2010 study published in Pediatrics.
The Vaccine Safety Datalink - which we used to conduct both the study of 1-2 year olds and the study of 4-6 year olds, is a premier example of how different managed care organizations can leverage their electronic medical records to improve vaccine safety and monitoring.
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Using cutting-edge illumination technology, Professor Ofer Levi and his research students from the Institute of Biomaterials & Biomedical Engineering (IBBME) and The Edward S. Rogers Sr. Department of Electrical & Computer Engineering (ECE)
have developed a new cost-effective neural imaging system.It allows researchers to make much more complex maps of the brain with just one camera and one imaging system. The team's initial findings, released this week in Biomedical Optics Express, demonstrate that this new technology may one day transform the way researchers view the human brain.
Developed from the same technology that lights up our cell phones and computers, this unique system uses Vertical Cavity Surface Emitting Lasers (VCSEL): low-cost, easily-tested, miniature microchip lasers mounted on an extremely fast, sensitive camera, which allows the operator to switch the lasers on and off with extraordinary speed and precision. This rapid light manipulation (at a rate of approximately 1x/millisecond) means that the brain can be mapped with greater sophistication and precision - much more quickly. Results published in Professor Levi's article, for instance, demonstrate that this imaging technology is able to classify both veins and arteries simultaneously - something never before accomplished.
Professor Levi asserts that this new, "agile system" is only the beginning; he plans to adapt the technology into a portable model, which would enable researchers to conduct studies with "freely behaving," or non-anesthetized, animals. While other portable neural mapping systems already exist, Professor Levi's multi-modality technology mean that blood flow, oxygenation and florescence - the three components of the human brain that researchers look at, which currently requires three different imaging systems - can be mapped simultaneously.
Professor Levi's research collaborators, IBBME Professor Tom Chau, Dr. Peter Carlen at Toronto Western Hospital, Dr. Taufik Valiant at Toronto Western Hospital, and Dr. Bojana Stefanovic at Sunnybrook Health Sciences Centre, are keeping a close eye on this technology towards its potential future applications. Dr. Carlen's lab, for example, participated in experiments to map epileptic seizures in living animals. Although this new technology requires further testing, Dr. Carlen said, "its' potential is enormous and exciting."
Professor Levi's imaging system may someday enable researchers to pinpoint metabolic changes in the brain that occur just moments prior to an epileptic seizure, or may help doctors map the brain's "areas of eloquence," those areas that need to remain untouched, prior to surgery on epileptic patients. Currently these areas are mapped electrically, over sometimes-extended periods of time and with great discomfort to the patient.
Other applications may include helping researchers create brain-interface technology that would allow researchers "to decode [disabled children's] intentions in the absence of speech and gestures," said Professor Chau in a statement. Professor Levi and his former U of T Master's student, Elizabeth Munro, submitted a patent for the new technology adaptations through the University of Toronto Innovation Group in January.
University of Toronto Faculty of Applied Science & Engineering
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