Abstract B137: Preclinical evaluation of a Wilms’ tumor protein 1-targeted interleukin-15 dendritic cell vaccine: T-cell activity and batch production

Abstract

Encouraging results from clinical trials demonstrate that dendritic cell (DC) vaccination is a valuable tool in cancer immunotherapy. Empowering DC vaccine immunogenicity to improve clinical outcome is at center stage in the rapidly evolving immunotherapeutic landscape. Developing a unique type of DC vaccine, so-called interleukin (IL)-15 DCs generated with IL-15 and strong immune stimulating maturation signals, we could demonstrate superior in vitro activities at both adaptive as well as innate immunity as compared to gold-standard IL-4 DCs. In this light, IL-15 DCs are capable of activating NK cells and gamma-delta T-cells, whereas IL-4 DCs are not. Designed to induce durable antitumor T-cell immunity, this pre-clinical research focuses on the improvement of Wilms’ Tumor protein 1 (WT1)-targeted T-cell activity. The WT1 antigen is overexpressed in a wide variety of human cancers and thus appears to fulfill the criteria of a universal tumor-associated antigen. The capacity of our novel IL-15 DCs to induce WT1-specific immunity is assessed using two in-house developed tumor antigen-specific T-cell assays. The first series of experiments demonstrate in a head-to-head comparison that WT1 mRNA-electroporated IL-15 DCs perform at least as well as IL-4 DCs in triggering a WT1 T-cell receptor (TCR)-transfected T-cell line. Using an autologous primary TCR-engineered CD8+ T-cell approach, we are now comparing their WT1-specific antitumor function. With its unique characteristics, including IL-15-transpresentation and interferon-gamma secretion, IL-15 DCs are expected to significantly promote WT1-specific T-cell-mediated tumor cell killing. Enabling its clinical application, we also evaluated the upscaled IL 15 DC vaccine production and cryopreservation processes. We were able to employ the three-day culture protocol in clinically suitable culture flasks. In addition, the use of an optimized cryopreservation medium results in a pre- to-post cryopreservation yield of 81.3 ± 7.4 % with a preserved phenotype and functionality. High-scale production and cryopreservation allows for the implementation of DC vaccination in multimodal treatment schedules. Underscoring the tumor antigen-specific T-cell-stimulating capacity among previously described superior characteristics and warranting batch production of patient-specific DC vaccines, further strengthens the impetus to bring WT1-loaded IL-15 DCs to the clinic. Citation Format: Maarten Versteven, David Damoiseaux, Diana Campillo-Davo, Heleen Van Acker, Hans De Reu, Sebastien Anguille, Zwi N Berneman, Evelien L Smits, Viggo F Van Tendeloo, Eva Lion. Preclinical evaluation of a Wilms’ tumor protein 1-targeted interleukin-15 dendritic cell vaccine: T-cell activity and batch production [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B137.