Endoscopic Ultrasound-Guided Fine-Needle Injection of Immature Dendritic Cells Into Advanced Pancreatic Cancer Refractory to Gemcitabine: A Pilot Study

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To the Editor:New therapies for pancreatic cancer are needed to improve its prognosis. Immunotherapy, a novel approach, has been investigated for pancreatic cancer.1Dendritic cells (DCs), used in DC vaccine therapy against cancer, are potent antigen-presenting cells for induction of primary T-cell-dependent immune responses.2 Many strategies for delivering antigens into DCs have been established in murine models and clinically tried. Synthetic peptide approaches require identification of tumor-specific antigens for individual tumors and demonstration of their recognition by cytotoxic T lymphocytes. However, because cancer has many unknown antigens, antigenic peptides and cytotoxic T-lymphocyte epitopes presented by human pancreatic cancer remain largely unidentified. We intratumorally injected unloaded DCs into pancreatic cancer cells; they acquire and process tumor antigens in situ, migrate to regional lymphoid organs, and initiate a strong tumor-specific immune response. Such intratumoral injection appears preferable to intravenous or intradermal injections.Interventional endoscopic ultrasound (EUS) can approach pancreatic cancer cells using EUS-guided fine-needle injection (EUS-FNI) technique.1 We performed EUS-FNI of DCs to investigate the feasibility, safety, and clinical response of EUS-FNI of unpulsed immature DCs into the pancreatic cancer refractory to systemic administration of gemcitabine. This report of a pilot clinical study to inject unpulsed immature DCs into advanced pancreatic cancer cells is believed to be the first. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethical committee of Fukushima Medical University. All patients provided informed consent before treatment.Seven patients had been unsuccessfully treated (gemcitabine) unresectable pancreatic cancer: 7 stage IV patients with multiple liver metastasis and/or artery involvement and 2 with malignant ascites. All patients had histologically proven intraductal adenocarcinoma by EUS-guided fine-needle aspiration. For preparation of DCs, the patients were leukophoresed to obtain a neutrophil-depleted fraction of peripheral blood mononuclear cells from approximately 6 to 7 L of blood. Countercurrent elutriation was then performed to separate cells into monocyte-rich and lymphocyte-rich fractions and used or cryopreserved as described previously.3 Using granulocyte-macrophage colony-stimulating factor and interleukin 4, patients' peripheral monocytes generated immature DCs.4 Patients received intratumoral injection of 10 billion or more immature DCs at 2 to 3 sites using EUS-FNI. Five of 7 patients received irradiation therapy before initial EUS-FNI of DCs to induce apoptosis and necrosis and to produce tumor-associated antigens for DC cross-presentation. DC was administrated on days 1, 8, and 15. The cycles were repeated every 28 days as much as possible. Physical and laboratory examinations assessed the potential vaccine toxicity. Clinical end points were CA-19-9, tumor response, and survival. Standard clinical response criteria were applied. Complete response was complete regression of all lesions lasting at least 1 month. Partial response (PR) was a greater than 50% decrease of lesions lasting more than 1 month. Mixed response (MR) was a regression of main pancreatic tumors, whereas other lesions remained stable or progressed. Stable disease (SD) was defined as a less than 25% size reduction with no newly developed lesions for more than 1 month. Progressive disease (PD) was defined as increase of more than 25% in the sites of the metastatic lesions or the occurrence of new lesions.Table 1 shows that all DC injections were tolerated without clinical toxicity. No complication associated with EUS-FNI procedure was noted. The CA-19-9 level decreased in 3 patients; 3 had MRs (2 with malignant ascites). Median survival was 9.9 months, although previous studies reported 8 to 9 months as the mean for chemotherapy patients5; patients with peritonitis carcinomatosa face shorter survival.

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