RESUMEN
The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.
Asunto(s)
Antígenos B7/inmunología , Carcinoma Ductal Pancreático/terapia , Inmunoterapia Adoptiva/métodos , Neuroblastoma/terapia , Neoplasias Ováricas/terapia , Neoplasias Pancreáticas/terapia , Receptores Quiméricos de Antígenos/inmunología , Animales , Antígenos B7/genética , Antígeno B7-H1/inmunología , Antígenos CD28/inmunología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Técnicas de Cocultivo , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Masculino , Ratones Endogámicos C57BL , Neuroblastoma/genética , Neuroblastoma/inmunología , Neuroblastoma/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Receptores Quiméricos de Antígenos/genética , Transducción de Señal , Carga Tumoral , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Unlike other gastrointestinal tumors, lymph node involvement has not consistently been a negative prognostic factor for survival in patients with duodenal adenocarcinoma. Our aim is to examine prognostic factors in patients who underwent a curative resection of their duodenal adenocarcinoma. METHODS: A retrospective review of 169 patients diagnosed with primary duodenal lesions between 1982 and 2010 was performed, of whom 103 were treated with curative intent. Clinico-pathologic factors were evaluated. RESULTS: A potentially curative resection was performed in 103 patients with a median age of 67 years (range, 22-91). Perineural and lympho-vascular invasion were identified in 30 (29.1%) and 39 patients (37.9%), respectively. Median follow-up was 26.5 months. The 5-year overall survival was 62% vs. 25% for patients with or without nodal metastases (p < 0.001) and 56% vs. 19% for patients with or without perineural invasion (p < 0.001), respectively. Lymph node ratio, type of resection, and size of tumor failed to stratify prognosis. By multivariate analysis, perineural invasion was the most powerful independent predictor of survival (HR, 2.520; CI, 1.361-4.664). CONCLUSIONS: Perineural invasion is a stronger predictor for recurrence and survival than tumor size, depth of infiltration, lymph node involvement, and type of resection in patients with duodenal adenocarcinoma.