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2012 TTCF Grand Prize Recipient
Tom Belle Davidson, M.D.
Assistant Professor of Pediatrics
Division of Pediatric Hematology/Oncology
Dendritic Cell Vaccination for Pediatric High-Grade Glioma Patients
Brain tumors in the pediatric population have poor prognosis and account for the highest mortality rate of all childhood cancers. Those who do achieve long-term survival often suffer from severe side
effects, including intellectual impairment, motor and hormonal deficits, and growth delay, from aggressive therapies. Of all the pediatric brain tumors, high-grade gliomas remain the largest challenge, with few treatment options available and an overall five-year survival rate of just 10-30 percent.
We have seen little improvement over the last 30 years in the ability to provide a cure for this devastating condition. The lack of effective treatment remains a largely unmet medical need and highlights the urgency for novel and effective therapies. A possible alternative to conventional toxic cancer treatments is utilizing a patient's own immune system to target and eliminate tumor cells. This approach has the potential to completely transform our traditional methods of attacking cancer, which are laden with extreme side effects, and may lead to a new era of safer, more personalized anti-cancer treatment.
In this study, immune system cells (dendritic cells - DCs) taken from the patient's own blood will be treated with broken-down cells isolated from his/her tumor tissue during surgery. By combining DCs and tumor cells, we will stimulate the child's own immune system to recognize and destroy the intracranial brain tumor. These stimulated DCs will then be injected back into the patient as a vaccine in order to teach the host immune system to identify the malignant brain tumor cells as "foreign" to the body. Theoretically, this method will lead to the patient's own immune system attacking any residual tumor cells.
UCLA has been at the forefront of this field with the use of DC-based therapies for adult brain tumors in pre-clinical models and in clinical trials. Previous studies focused on vaccination in adult patients with high-grade gliomas. A pilot study led by Dr. Theodore Moore and enabled by Today's and Tomorrow's Children Fund (TTCF) in 2007 demonstrated both feasibility and tolerability among pediatric patients, establishing a foundation for the next phase of research. We now have the expertise and staff resources to move forward, optimizing the use of DC vaccination in a larger number of patients at multiple institutions, while using small amounts of DNA obtained from their tumor tissue to search for specific genetic mutation signatures. Funding from TTCF will help foster this pioneering research, the results of which may lead to improved targeted therapy for children with high-grade gliomas, and ultimately to vaccines being incorporated in standardized care.
Furthermore, we plan to investigate the use of Imiquimod, a topical immunomodulatory compound, that stimulates the innate immune system and has been shown to display antiviral and antitumor activity. We hypothesize that the combination of DC anti-tumor vaccination and applied Imiquimod cream to the vaccination site in children with high-grade gliomas will be tolerable and may induce better immune responses. Moreover, we expect subsequent improved outcomes with fewer toxic side effects than current standard therapies with chemotherapeutics and radiation alone.
2012 TTCF Prize Recipient
Joyce Wu, M.D.
Associate Professor
Division of Pediatric Neurology
High-Frequency Oscillations: A Potential Noninvasive Biomarker of Pediatric Epilepsy
Childhood epilepsy is a particularly disabling group of chronic disorders. With a 1-percent incidence of epilepsy in the general population, about 50 percent begins in the pediatric years (18 and younger). While the incidence is four-fold that of breast cancer, the 2011 National Institutes of Health funding for pediatric epilepsy was less than one-tenth of that for breast cancer. Furthermore, in a significant 25-30 percent of children, their epilepsy cannot be controlled with anticonvulsants, which means about a half-million youngsters in the United States continue with frequent seizures despite multiple concurrent medications. In addition to disabling seizures, these children often have other epilepsy related conditions, such as cognitive impairment and autism, a triple threat that takes an emotional and financial toll on families, as well as schools and society. Despite the introduction of multiple new anticonvulsants over the last decade, the proportion of intractable epilepsy has remained relatively unchanged.
Unfortunately, the causes of medically refractory epilepsy remain largely unknown. A reliable biomarker for epileptogenesis (development of epilepsy) that is able to assess, monitor, and even predict the condition is needed; the molecular basis underlying this marker will open the door to new treatment. High-frequency oscillations (HFOs) have emerged as such a potential biomarker. First seen in animal models, HFOs are an ultra-fast brain electrical activity (100-500 Hz), which is localized in the seizure onset zone and predicts which animals will develop epilepsy. Findings from our group advanced this field by first finding HFOs in children with epilepsy. We also were the first to detect HFOs throughout the brain; they were previously limited to one particular structure. Compared to HFO
detection with invasive surgical implants inside patients' heads for days to weeks as part of their epilepsy surgery evaluation, our findings significantly reduced that time to about 10 minutes just prior to resection in the operating room, without the risky surgical implantation. We also correlated the complete surgical resection of HFOs with seizure freedom, probably the most resounding feature of such a biomarker.
Our current plan to expand the concept of HFOs as a biomarker is two-fold: 1) to further establish HFOs as a spatially localizing biomarker of the epileptogenic zone, ultimately leading to noninvasive localization with scalp electroencephalographs (EEGs); and 2) to establish HFOs as a temporally predictive biomarker of epileptogenesis, by correlating its presence with later-life epilepsy in preepileptic
high-risk children due to birth hypoxia, traumatic brain injury, and tuberous sclerosis complex (formation of tumors in various organs). Additionally, the first objective includes "live" HFO interpretation in the operating room, which will enable brain tissue resected during surgery to be studied, potentially leading to a better understanding of epileptogenesis and new antiepileptic drug design. Both objectives hold promise for future clinical trials for better surgical mapping and potential disease-modifying therapy to prevent epileptogenesis altogether, not merely stopping seizures with anticonvulsant medications. HFO detection requires special equipment and recording parameters, and the analysis is 10 times more time and labor-intensive than traditional EEGs. Thus, both personnel and the EEGs themselves depend heavily on research dollars. Support from Today's and Tomorrow's Children Fund will greatly empower us to move forward on these research objectives, which may establish HFOs as a noninvasive, spatially localizing, and temporally predictive biomarker for pediatric epilepsy - unimaginable just a decade ago.
2012 TTCF Prize Recipient
Julian Martinez-Agosto, M.D., Ph.D.
Assistant Professor
Department of Human Genetics and Department of Pediatrics
Genetic Risk Factors for Autism and Cancer Predisposition
Autism and cancer are the most common causes of illness in children. One out of every 110 children
will be diagnosed with autism, and cancer is the leading cause of death in those aged one to 14. Both conditions have been increasing in incidence over the past decade.
Autism can be inherited; siblings of children with this condition are 19 percent at risk of also having it, often because of delays in diagnosis. While recent advances in diagnosis and treatment have enhanced developmental outcomes, the causes for autism remain largely elusive. The study of rare genetic conditions with signs of autism, however, provides some insight. One group of genetic entities that can present with autism is overgrowth syndromes. They are characterized by large size at birth, excessive postnatal growth, and increased weight, length, and/or head circumference for age and also are associated with an increased risk of specific solid tumors and leukemia. A late diagnosis may cause affected children to develop tumors that are too advanced for treatment to be effective. In this sense, a prompt diagnosis could have a significant positive impact.
While the causes in a limited number of cases have been revealed, the genetic basis for the vast majority is unknown. Our laboratory studies focus on genetic conditions in which children experience overgrowth (their bodies grow faster than their peers'). A subset of these children have autism and large head-size. Based on this knowledge, we have developed a clinical website that provides related information to parents of such children and promotes their evaluation at UCLA. We now use the most novel technologies to identify the genetic changes in order to expand our understanding of the causes of autism and, in some cases, predisposition to cancer. Support from Today's and Tomorrow's Children Fund will enable us to use "Next Generation Whole Exome" sequencing and chromosomal microarray analysis to identify mutations in pediatric patients with overgrowth syndromes. This technology will allow us to look at
each letter in a patient's genes, sequencing DNA to identify rare mutations that are predicted to cause autism, overgrowth, and/or cancer predisposition. Once we have identified the affected genes, we will be able to pursue additional funding to analyze their function.
We collaborate with a psychiatrist, neurologist, and oncologist, who provide genetic services to overgrowth patients.
Our findings are expected to enhance our understanding of the genetic risk factors for autism and the biology of pediatric growth disorders, as well as provide new potential targets for therapies. Revealing the causative genes will immediately lead to a medical test that will allow physicians to identify those children at highest risk. These results also will provide parents with critical information for planning future pregnancies. Finally, clarifying the genetic basis of how our bodies grow and develop will allow for the 1) harnessing of regenerative capabilities of tissues, 2) elucidation of the causes of cancer, and 3) further insight into the process of childhood maturation.
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