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Precision Cancer Immunotherapy: Optimizing Dendritic Cell-based Strategies to Induce Tumor Antigen-specific T-cell Responses Against Individual Patient Tumors

Osada, Takuya*; Nagaoka, Koji; Takahara, Masashi; Yang, Xiao Yi*; Liu, Cong-Xiao*; Guo, Hongtao*; Roy Choudhury, Kingshuk; Hobeika, Amy*; Hartman, Zachary*; Morse, Michael A.§; Lyerly, H. Kim*

doi: 10.1097/CJI.0000000000000075
Basic Studies
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SDC

Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy.

Supplemental Digital Content is available in the text.

Departments of *Surgery

§Medicine, Duke University Medical Center

Department of Biostatistics & Bioinformatics, Duke University, Durham, NC

Medinet Medical Institute, MEDINET Co., Ltd, Tokyo, Japan

Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.immunotherapy-journal.com.

Reprints: Takuya Osada, 433a, MSRB1, Research DR, Durham, NC 27710 (e-mail: osada001@mc.duke.edu).

Received November 17, 2014

Accepted January 20, 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.