CSF-1R-Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy.
J Immunol
; 197(1): 179-87, 2016 07 01.
Article
en En
| MEDLINE
| ID: mdl-27217585
ABSTRACT
Cancer immunotherapies are increasingly effective in the clinic, especially immune checkpoint blockade delivered to patients who have T cell-infiltrated tumors. Agonistic CD40 mAb promotes stromal degradation and, in combination with chemotherapy, drives T cell infiltration and de novo responses against tumors, rendering resistant tumors susceptible to current immunotherapies. Partnering anti-CD40 with different treatments is an attractive approach for the next phase of cancer immunotherapies, with a number of clinical trials using anti-CD40 combinations ongoing, but the optimal therapeutic regimens with anti-CD40 are not well understood. Pancreatic ductal adenocarcinoma (PDA) is classically resistant to immunotherapy and lacks baseline T cell infiltration. In this study, we used a tumor cell line derived from a genetically engineered mouse model of PDA to investigate alterations in the sequence of anti-CD40 and chemotherapy as an approach to enhance pharmacological delivery of chemotherapy. Unexpectedly, despite our previous studies showing anti-CD40 treatment after chemotherapy is safe in both mice and patients with PDA, we report in this article that anti-CD40 administration <3 d in advance of chemotherapy is lethal in more than half of treated C57BL/6 mice. Anti-CD40 treatment 2 or 3 d before chemotherapy resulted in significantly increased populations of both activated myeloid cells and macrophages and lethal hepatotoxicity. Liver damage was fully abrogated when macrophage activation was blocked using anti-CSF-1R mAb. These studies highlight the dual nature of CD40 in activating both macrophages and T cell responses, and the need for preclinical investigation of optimal anti-CD40 treatment regimens for safe design of clinical trials.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
/
Fallo Hepático
/
Receptor de Factor Estimulante de Colonias de Macrófagos
/
Antígenos CD40
/
Carcinoma Ductal
/
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos
/
Inmunoterapia
/
Anticuerpos Monoclonales
Tipo de estudio:
Etiology_studies
/
Guideline
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Immunol
Año:
2016
Tipo del documento:
Article