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CSF-1R–DependentLethal HepatotoxicityWhen Agonistic CD40Antibody Is Givenbefore but Not afterChemotherapy Katelyn T. ByrneNathan H. LeisenringDavid L. Bajor2016 год

CSF-1R–Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy
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Аннотация: 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.
Год издания: 2016
Авторы: Katelyn T. Byrne, Nathan H. Leisenring, David L. Bajor, Robert H. Vonderheide
Издательство: American Association of Immunologists
Источник: The Journal of Immunology
Ключевые слова: Cancer Immunotherapy and Biomarkers, Cancer Cells and Metastasis, Cancer, Stress, Anesthesia, and Immune Response
Другие ссылки: The Journal of Immunology (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)