Dendritic Cells Pre-Pulsed with Wilms' Tumor 1 in Optimized Culture for Cancer Vaccination.

Terutsugu Koya,Tomohisa Kato,Shunsuke Kojima,Ryu Yanagisawa,Haruo Sugiyama,Shigeo Koido,Kenichi Yoshida,Asuka Watanabe,Ippei Date,Shigetaka Shimodaira,Misa Togi,Takuya Sakamoto,Haruhiko Kawaguchi

doi:10.3390/pharmaceutics12040305

Abstract

With recent advances in cancer vaccination therapy targeting tumor-associated antigens (TAAs), dendritic cells (DCs) are considered to play a central role as a cell-based drug delivery system in the bioactive immune environment. Ex vivo generation of monocyte-derived DCs has been conventionally applied in adherent manufacturing systems with separate loading of TAAs before clinical use. We developed DCs pre-pulsed with Wilms’ tumor (WT1) peptides in low-adhesion culture maturation (WT1-DCs). Quality tests (viability, phenotype, and functions) of WT1-DCs were performed for process validation, and findings were compared with those for conventional DCs (cDCs). In comparative analyses, WT1-DCs showed an increase in viability and recovery of the DC/monocyte ratio, displaying lower levels of IL-10 (an immune suppressive cytokine) and a similar antigen-presenting ability in an in vitro cytotoxic T lymphocytes (CTLs) assay with cytomegalovirus, despite lower levels of CD80 and PD-L2. A clinical study revealed that WT1-specific CTLs (WT1-CTLs) were detected upon using the WT1-DCs vaccine in patients with cancer. A DC vaccine containing TAAs produced under an optimized manufacturing protocol is a potentially promising cell-based drug delivery system to induce acquired immunity.

Highlights

Despite significant advances in cancer therapy such as surgical techniques, radiotherapy, and systemic therapy including immune checkpoint inhibitors [1,2,3,4,5,6], it remains extremely challenging to treat advanced cancers involving organ systems and distant metastasis
We evaluated the induction of Wilms’ tumor 1 (WT1)-specific cytotoxic T lymphocytes (CTLs) in cancer patients who received WT1-dendritic cells (DCs) administration
We established a protocol for the preparation of WT1-DCs pre-pulsed with WT1 peptides in optimized culture maturation

Summary

Introduction

Despite significant advances in cancer therapy such as surgical techniques, radiotherapy, and systemic therapy including immune checkpoint inhibitors [1,2,3,4,5,6], it remains extremely challenging to treat advanced cancers involving organ systems and distant metastasis. Therapeutic peptide vaccines targeting tumor-associated antigens (TAAs) for cancer immunotherapy have been in development for decades [7]. Wilms’ tumor 1 (WT1) molecules are expressed in various types of solid tumors; a peptide vaccination targeting this molecule has priority as an immunotherapy for cancer patients [10]. Hailemichael et al reported that incomplete Freund’s adjuvant, Montanide ISA51, in cancer peptide vaccines induced persisting vaccine depots [11]. Montanide ISA51 was used in peptide formulation [9], triggers specific T-cell sequestration, dysfunction, and deletion at the vaccination site. Peptide vaccination may be insufficient to recruit TAAs specific cytotoxic T lymphocytes (CTLs) to tumor sites, appropriate adjuvants and/or delivery systems may be useful to exert antitumor immunity

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