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

Abstract

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.

The effects of dendritic cell-based vaccines in the tumor microenvironment: Impact on myeloid-derived suppressor cells

“…MoDC vaccines loaded with TAAs demonstrated the stimulation of a preexisting immune response against TAAs in children, adolescents, and young adults with sarcoma tumors in a phase I/II clinical trial. Interestingly, one of those patients had low levels of MDSCs and Tregs prior to vaccination and experienced significant regression of metastatic lesions after a second disease relapse ( 133 ). A similar vaccine was tested in a clinical trial involving metastatic melanoma patients, but M-MDSCs increased after vaccination and were inversely associated with survival ( 129 ), demonstrating their immunosuppressive role.…”

Ewing Sarcoma Meets Epigenetics, Immunology and Nanomedicine: Moving Forward into Novel Therapeutic Strategies

“…Cancer vaccines stimulate the immune system typically by recognizing tumor-associated antigens and include peptide or dendritic cell vaccines loaded with tumor lysate or pulsed with antigenic peptides. On this basis, a vaccine made of patient-derived dendritic immune cells loaded with autologous tumor lysate or tumor antigens ex vivo has been shown to activate an antitumor response, although poor response in phase I/II studies in EWS and other soft tissue sarcomas [ 138 ]. New efforts are focused on combining these vaccines with chemotherapeutic regimens.…”

Recent Advances in Experimental Dendritic Cell Vaccines for Cancer

“…Patients with recurrent or refractory Ewing’s sarcoma who received intradermal vaccine administration based on moDC loaded with tumor lysate did not have a pronounced clinical response, however, some of them showed activation of the T-cell immune response. Probably disappointing clinical response data are associated with prior treatment, which had a serious immunosuppressive effect, as well as advanced disease and extensive lesions ( 39 ).…”