A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma.

T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2-7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

Resultados de la estimulación del nervio vago en pacientes con epilepsia farmacorresistente en un centro de referencia nacional de epilepsia / Results of vagal nerve stimulation in patients with pharmacoresistant epilepsy in a national epilepsy referral centre

Objetivos. Describir los resultados clínicos y complicaciones derivados de la estimulación vagal en pacientes con epilepsia farmacorresistente no tributaria de otras modalidades de tratamiento quirúrgico, desde el primer implante en un centro de referencia nacional. Pacientes y métodos. Se realizó un análisis retrospectivo de los pacientes implantados en nuestro centro y se extrajeron datos relativos a las características basales de su epilepsia y complicaciones derivadas. Resultados. Se incluyeron 32 nuevos implantes en 31 pacientes, con una edad media de 34 años, evolución de enfermedad de 29,3 años, tres fármacos antiepilépticos prequirúrgicos y 4,03 años de seguimiento. Las crisis parciales complejas (71,9%) y criptogénicas (59,4%) fueron el tipo y la etiología de crisis más frecuentes. El 75% no tenía antecedentes quirúrgicos de epilepsia. Un 43,8% presentó mejoría igual o superior al 50%, mayor en las epilepsias parciales complejas (p = 0,22) y la etiología criptogénica. No se halló asociación estadística entre ajustes de medicación y frecuencia de las crisis. Los efectos secundarios encontrados fueron disfonía, ronquera y disfagia transitorias, y una asistolia intraoperatoria recuperada. Se realizó un recambio por ruptura de hardware postraumática. Un paciente con paresia preexistente de cuerda vocal presentó estridor laríngeo que requirió ajuste de intensidad, y se produjo una retirada del sistema por disfunción. En el 84,4%, la tolerancia fue excelente. Conclusiones. Constituye un tratamiento efectivo para mejorar significativamente la frecuencia de crisis de los pacientes farmacorresistentes y con contraindicación para otras modalidades de tratamiento quirúrgico. Se precisan futuros estudios para predecir la respuesta individual de cada paciente, optimizar las indicaciones y mejorar la relación coste/beneficio (AU)

Aim. To describe clinical results and complications derived from vagal nerve stimulation therapy in drug resistant epileptic patients unsuitable for other surgical treatments, since the first implant in an epilepsy national referral centre. Patients and methods. A retrospective analysis of the patients implanted in our centre was held. Data related to baseline characteristics of their epilepsy and therapy complications was collected. Results. 32 new implants in 31 patients are included, mean age of 34 years, 29.3 years of disease evolution, three antiepileptic drugs at surgery and a postoperative follow-up of 4.03 years. Complex partial seizures types (71.9%) and cryptogenic aetiology (59.4%) were the most frequent. 75% of patients hadn’t history of previous epilepsy surgery. 43.8% of patients had a seizure frequency improvement above 50%, with a better response in patients with complex partial seizures (p = 0.22) and cryptogenic aetiology. None statistical significance was found between antiepileptic drugs and seizure frequency. Dysphonia, hoarseness and dysphagia, mostly transient, were the side effects registered. There was an asystole during surgery, completely recovered. One device was replaced due to hardware rupture after a seizure related trauma, one had to be adjusted due to a previous vocal cord paresis, and one dysfunctioning device was removed. In 84.4% the tolerance was excellent. Conclusions. Vagal nerve stimulation is an effective treatment for significant seizure frequency improvement of resistant patients untreatable with other medical or surgical treatments. Further studies are needed to predict the individual response of each patient to therapy and optimizing indications, therefore contributing to cost/benefit optimization (AU)