The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC) constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses. Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an ALVAC-CEA-B7.1 vaccine (4.5 x 10(6), 4.5 x 10(7), and 4.5 x 10(8) plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA-B7.1 at doses up to 4.5 x 10(8) PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-gamma enzyme-linked immunoassay spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses. This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1 to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with tolerable toxicity.

Summary:Status epilepticus (SE) is a significant neurological emergency that occurs most commonly in children. Although SE has been associated with an elevated risk of brain injury, it is unclear from clinical studies in whom and under what circumstances brain injury will occur. The purpose of this review is to evaluate the effects of age on the consequences of SE. In this review, we focus mainly on the animal data that describe the consequences of a single episode of SE induced in the adult and immature rat brain. The experimental data suggest that the risk of developing SE-induced brain damage, subsequent epilepsy and cognitive deficits in large part depends on the age in which the SE occurs. Younger rats are more resistant to seizure-induced brain damage than older rats; however, when SE occurs in immature rats with abnormal brains, there is an increase in the severity of seizure-induced brain injury. Better understanding of the pathophysiologic mechanisms underlying the age-specific alterations to the brain induced by SE will lead to the development of novel and effective strategies to improve the deleterious consequences.

Early in life, SE can influence the outcome of a subsequent focal ischemic insult in adulthood. The extent of the infarct is related to the duration and cause of SE. Prolonged SE induced by KA worsens the outcome, whereas FE-SE has a neuroprotective effect.

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