Dendritic cell vaccination and CD40-agonist combination therapy licenses T cell-dependent antitumor immunity in a pancreatic carcinoma murine model.

Journal for Immunotherapy of Cancer
Sai Ping LauCasper H J van Eijck

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to treatment including checkpoint-blockade immunotherapy. We hypothesized that a bimodal treatment approach consisting of dendritic cell (DC) vaccination to prime tumor-specific T cells, and a strategy to reprogram the desmoplastic tumor microenvironment (TME) would be needed to break tolerance to these pancreatic cancers. As a proof-of-concept, we investigated the efficacy of combined DC vaccination with CD40-agonistic antibodies in a poorly immunogenic murine model of PDAC. Based on the rationale that mesothelioma and pancreatic cancer share a number of tumor associated antigens, the DCs were loaded with either pancreatic or mesothelioma tumor lysates. Immune-competent mice with subcutaneously or orthotopically growing KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) PDAC tumors were vaccinated with syngeneic bone marrow-derived DCs loaded with either pancreatic cancer (KPC) or mesothelioma (AE17) lysate and consequently treated with FGK45 (CD40 agonist). Tumor progression was monitored and immune responses in TME and lymphoid organs were analyzed using multicolor flow cytometry and NanoString analyzes. Mesothelioma-lysate loaded DCs generated cross-reactive tumor-antige...Continue Reading

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Datasets Mentioned

BETA
SRX6812144

Methods Mentioned

BETA
surgical resection
RNA-seq
flow cytometry
PCR
PMA
ELISA

Clinical Trials Mentioned

NCT03214250
NCT02588443
NCT03329950

Software Mentioned

GraphPad Prism
R
Ventana
geNorm
Treestar
FlowJo
RStudio
GSEA

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