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2013 TTCF Grand Prize Recipient

Clinical Instructor of Pediatrics, Division of Pediatric Hematology/Oncology

Development of an immunotherapy protocol with persistent anti-leukemic activity

New therapeutic options are needed for pediatric leukemia patients in order to decrease side effects and mortality. Leukemia is a cancer of the white blood cells, and even with the recent advances in chemotherapy, patients with refractory or relapsed disease still have less than a 50% chance of survival. Hematopoietic stem-cell transplantation is usually indicated as the treatment option for those patients, replacing their immune cells with cells from a matched donor in an attempt to create an immune response against the cancer. This procedure can cause death or lifelong complications but still offers a cure for less than five in every 10 patients. After two years of full-time clinical work in Brazil, I realized that a cure for pediatric cancer would require relentless research, and thus I restarted my career in the United States as a physician-scientist.

Since joining UCLA, I have formed a team to help translate my research goals into reality; I am a member of the UCLA Bone Marrow and Stem Cell transplant team and have established collaborations with faculty members in the UCLA Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. For many decades, UCLA has been in the frontline of research on immunological approaches to treat cancer. Building on that knowledge, this project proposes a new protocol to develop persistent anti-leukemic therapy; it transfers a gene into blood stem cells and originates multiple immune cells directly targeting CD19, a surface marker that is present in more than 95% of all leukemias and lymphomas. In other words, this process enables the patient's own blood stem cells to create a whole self-renewing immune system directed to destroy the cancer cells.

Multiple innovations are proposed through the use of cutting-edge laboratory techniques. Our main goal is to optimize the efficacy of cancer targeting with minimal toxicity and a safer profile. Using the patient's own cells instead of those from a matched donor has significant advantages. The modification of blood stem cells will persistently generate different immune cells targeting cancer, hopefully throughout life, enabling the patients' bodies to fight their cancers without chemotherapy drugs. Another breakthrough in cancer immunotherapy is the inclusion of a safety feature in the modification of the cells, creating a way to "turn-off" those cells in case of undesired side effects or late complications. The gene modification of the cells renders them sensitive to ganciclovir, an antiviral medication that has very limited adverse effects in human cells.

An investment from Today's and Tomorrow's Children Fund will help generate knowledge to support the advancement to clinical trials - a promise of new therapeutic options for patients for whom current treatments are not successful. Children will especially benefit from decreased side effects of cancer treatment, not only now, but also as they progress to adulthood. In addition, the possibility of using the patient's own cells will benefit adopted children and ethnic minorities, for whom the search for a matched donor for hematopoietic stem-cell transplantation is very limited. This study will improve therapeutic approaches and allow personalized therapy for all cancer patients, as the same methods could be customized to any type of cancer just by switching the target.

2013 TTCF Prize Recipient

Adjunct Professor, Division of Pediatric Neurology

Infection during pregnancy as a risk factor for the development of autism-associated epilepsy in children

Autism is a detrimental neuro-developmental disorder that affects approximately one out of 88 children in the United States. The economic burden of the disease is overwhelming: Costs of providing care are estimated at $1.4 million over the patient's lifetime. Such symptoms of autism as impaired social interaction, communication, and restricted behavior all impede proper integration of patients into society. 

Along with behavioral deficits, at least 1/3 of children with autism develop epilepsy. Such comorbidity (i.e., concurrent development of psychiatric impairments and seizures in the same patient) between autism and epilepsy poses an additional burden on children and worsens the prognosis of autism proper. Therefore, preventing seizures in these patients will in itself dramatically improve their quality of life. Causes that underlie the comorbidity, however, remain largely unknown and insufficiently explored, in large part due to the complexities associated with clinical studies, and to the disconnect between researchers involved in studying autism and those investigating epilepsy.

Although genetic causes of autism have been commonly accepted, many cases cannot be attributed to a genetic trait, suggesting the involvement of environmental factors. Recent epidemiological studies have established a strong association between viral infections (particularly flu) experienced by pregnant women and the development of autism in their children. Response of the immune system to infections consists of the induction of multiple components of inflammation (called cytokines) in blood and the placenta. Among these components, cytokine interleukin-6 (IL-6) has been identified as a key factor determining the development of autism in children. Since viral infections are far more widespread that genetic abnormalities, such infections may constitute a more common cause of autism than genetic mutations. It is not known, however, if infections during pregnancy pose a risk for the development of epilepsy alongside autism, and, if they do, which mechanisms are responsible for the evolvement of seizures.

The present proposal pursues answering these questions through the development of a novel animal model of comorbidity between autism and epilepsy. First, we will induce viral infection in pregnant mice and will examine the offspring for the presence of epilepsy alongside autism, using specialized behavioral and electrographic tests. Next, we will examine the substrate of autism-associated epilepsy by studying specific morphological and biochemical brain abnormalities. Finally, we will examine which components of immune response in pregnant mice determine the evolvement of epilepsy. Our pilot experiments suggest that the combination of two factors of inflammation is both necessary and sufficient for the development of epilepsy in the offspring: cytokines IL-6 and interleukin-1beta (IL-1β). Therefore, we will a) measure levels of these cytokines in the blood of pregnant mice during viral infection and will correlate these levels with the development in the offspring of autism and epilepsy; b) block effects of these cytokines, using their specific antagonists; c) produce viral infection in mutant mice that lack either IL-6 or IL-1β; and d) administer pregnant mice with IL-6, IL-1β, or their combination in lieu of viral infection. In each case, the offspring will be examined for the presence of autism and of epilepsy.

Funding from Today's and Tomorrow's Children Fund will greatly enhance progress on this study, which is expected to have two practical outcomes in the diagnosis and prevention of autism-associated epilepsy. First, measuring levels of the identified candidate factors in the blood of pregnant women exposed to infection will allow us to reliably predict the risk of the development of autism-associated epilepsy even before the child's birth. Second, based of the outcomes of the diagnostic test, treating expecting mothers during viral infections with selective blockers of the two cytokines will significantly reduce the risk of the development of epilepsy in their children.


2013 TTCF Prize Recipient

Clinical Assistant Professor, Division of Neonatology

Prevention and Treatment of Intestinal Failure-Associated Liver Disease in Newborns

Prematurity and congenital malformations are the number one and two causes of infant death. Approximately half-a-million premature babies and 5,000 infants with gastrointestinal congenital defects are born each year in the United States, and they are unable to take food by mouth. Intravenous nutrition is prescribed by doctors to provide fluids and calories. While this treatment is life-sustaining, it is associated with a potentially life-threatening complication, intestinal failure-associated liver disease (IFALD). Approximately 25-50% of premature babies and newborns with gastrointestinal disorders develop IFALD; about 10% require intravenous nutrition for a prolonged period of time - months to even a lifetime - because of a serious intestinal problem. IFALD can eventually progress to liver failure and death, and though liver and/or intestinal transplants can be lifesaving, they are not a perfect solution.

Safe and effective preventive strategies and treatments for IFALD are lacking. My goal is to help UCLA provide cutting-edge care to children and improve their quality of life; for the past five years, my research has focused on how to best prevent and treat IFALD in order to avoid liver failure, the need for transplant, and death. My research is cross-disciplinary; I work with a team of gastroenterologists, surgeons, and neonatologists at UCLA and other institutions. Specifically, we have focused on the dose and type of fat in intravenous nutrition, and our work indicates that a lower dose and/or a different type of intravenous fat than currently prescribed can prevent and treat IFALD.

I am conducting two multi-site, randomized, controlled trials to determine if giving premature babies and babies with congenital gastrointestinal disorders a decreased dose of soybean oil blocks IFALD, and if this possibility offsets the risk of poor growth. These studies will follow children until they are two years of age and collect information on how growth is affected by less fat in the newborn period. Also, in order to determine if changing the type of fat treats IFALD, we are conducting a study with intravenous fish oil. Soybean oil is made up of omega-6 fatty acids and compounds called phytosterols that are known to damage the liver. Fish oil, in comparison, is made of omega-3 fatty acids. We believe that children given less fat and/or fish oil will have more proteins and genes in their blood that protect their liver. Our data indicate that when fish oil is substituted for soybean oil, IFALD can be treated; we have provided 26 children with fish oil and will follow them for five years to determine if transplant-free survival is increased.

To better understand IFALD, research must: 1) discover safe, effective, and affordable treatments and 2) understand how these therapies work. My investigations are attempting to address these problems. If we are able to prevent IFALD and the need for transplant, human lives and healthcare dollars will be saved. In 2010, support from Today's and Tomorrow's Children Fund (TTCF) enabled preliminary data on the use of fish oil; a new investment from TTCF will be used to complete translational laboratory studies to determine how changes in dose and the type of fat alter specific proteins and genes in the blood, the next phase of critical research on this topic. Information gathered will allow us to conduct more sophisticated studies on liver tissue obtained from children with IFALD. In addition, we will complete long-term follow-up on these children. As of today, we have 140 preterm babies who received either low- or high-dose soybean oil. It is crucial for us to determine if their long-term neurodevelopment and growth are changed, as well as how a low-fat diet early in life can change a child's risk for disease - such as obesity, diabetes and cardiovascular disease - later on. Funds will be used, as well, to launch a new trial investigating oral fish oil, which may provide some advantages compared to intravenous fish oil. Oral fish oil is cheaper and can be provided at a higher dose, which may be beneficial for growth.


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