Assessment of Immune Response Following Dendritic Cell-Based Immunotherapy in Pediatric Patients With Relapsing Sarcoma

• Main Authors: Lenka Fedorova, Peter Mudry, Katerina Pilatova, Iveta Selingerova, Jana Merhautova, Zdenek Rehak, Dalibor Valik, Eva Hlavackova, Dasa Cerna, Lucie Faberova, Pavel Mazanek, Zdenek Pavelka, Regina Demlova, Jaroslav Sterba, Lenka Zdrazilova-Dubska
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-11-01
• Series: Frontiers in Oncology
• Subjects: dendritic cells; anticancer immunotherapy; dendritic-cell (DC)-based vaccine; pediatric sarcoma; academic clinical trials; immunomonitoring
• Online Access: https://www.frontiersin.org/article/10.3389/fonc.2019.01169/full

Monocyte-derived dendritic cell (DC)-based vaccines loaded with tumor self-antigens represent a novel approach in anticancer therapy. We evaluated DC-based anticancer immunotherapy (ITx) in an academic Phase I/II clinical trial for children, adolescent, and young adults with progressive, recurrent, or primarily metastatic high-risk tumors. The primary endpoint was safety of intradermal administration of manufactured DCs. Here, we focused on relapsing high-risk sarcoma subgroup representing a major diagnosis in DC clinical trial. As a part of peripheral blood immunomonitoring, we evaluated quantitative association between basic cell-based immune parameters. Furthermore, we describe the pattern of these parameters and their time-dependent variations during the DC vaccination in the peripheral blood immunograms. The peripheral blood immunograms revealed distinct patterns in particular patients in the study group. As a functional testing, we evaluated immune response of patient T-cells to the tumor antigens presented by DCs in the autoMLR proliferation assay. This analysis was performed with T-cells obtained prior to DC ITx initiation and with T-cells collected after the fifth dose of DCs, demonstrating that the anticancer DC-based vaccine stimulates a preexisting immune response against self-tumor antigens. Finally, we present clinical and immunological findings in a Ewing's sarcoma patient with an interesting clinical course. Prior to DC therapy, we observed prevailing CD8+ T-cell stimulation and low immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSC) and regulatory T-cells (Tregs). This patient was subsequently treated with 19 doses of DCs and experienced substantial regression of metastatic lesions after second disease relapse and was further rechallenged with DCs. In this patient, functional ex vivo testing of autologous T-cell activation by manufactured DC medicinal product during the course of DC ITx revealed that personalized anticancer DC-based vaccine stimulates a preexisting immune response against self-tumor antigens and that the T-cell reactivity persisted for the period without DC treatment and was further boosted by DC rechallenge.Trial Registration Number: EudraCT 2014-003388-39.