title: CSF-1R-Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy.
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.
authors.affiliation: Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Katelyn T
authors.initials: KT
authors.lastname: Byrne
authors.affiliation: Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Nathan H
authors.initials: NH
authors.lastname: Leisenring
authors.affiliation: Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: David L
authors.identifier: 0000-0003-2702-5008
authors.initials: DL
authors.lastname: Bajor
authors.affiliation: Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104 rhv@exchange.upenn.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000819:agonists*; D044584:Carcinoma, Ductal / Q000150:complications / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D002985:Clinical Protocols; D004347:Drug Interactions; D004358:Drug Therapy; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D017093:Liver Failure / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D010190:Pancreatic Neoplasms / Q000150:complications / Q000276:immunology / Q000628:therapy*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D016186:Receptor, Macrophage Colony-Stimulating Factor