Immunotherapy with dendritic cells loaded with glioblastoma stem cells: from preclinical to clinical studies

Abstract

Different approaches have been explored to raise effective antitumor responses against glioblastoma (GBM), the deadliest of primary brain tumors. In many clinical studies, cancer vaccines have been based on dendritic cells (DCs) loaded with peptides, representing one or more specific tumor antigens or whole lysates as a source of multiple antigens. Randomized clinical trials using DCs are ongoing, and results of efficacy are not yet available. Such strategies are feasible and safe; however, immune-suppressive microenvironment, absence of appropriate specific epitopes to target, and cancer immunoediting can limit their efficacy. The aim of this review is to describe how the definition of novel and more specific targets may increase considerably the possibility of successful DC immunotherapy. By proposing to target glioblastoma stem-like cells (GSCs), the immune response will be pointed to eradicating factors and pathways highly relevant to GBM biology. Preclinical observations on efficacy, and preliminary results of immunotherapy trials, encourage exploring the clinical efficacy of DC immunotherapy in GBM patients using high-purity, GSC-loaded DC vaccines.

Keywords: Cancer stem-like cells; Dendritic cells; Glioblastoma; Immunotherapy; NIBIT 2014.

Fig. 1

a Kaplan–Meier analysis showing that in vitro NS formation is associated with decreased survival in patients (p = 0.018). b Magnetic resonance imaging performed on nude mice 55 days after tumor implantation (upper panel) and histological analysis performed on xenograft gliomas (lower panel). c Kaplan–Meier analysis curves showing that DCs loaded with GSC lysate protect from GL261-GSC glioma a larger fraction of mice compared with DCs loaded with whole tumor lysates. d Real-time PCR performed on GSCs reveals that expression of nestin, GLAST, and OLIG2 is 8.1, 2.6, and 3.7 higher, respectively, compared to tumor (**p < 0.001, ****p < 0.0001)

Fig. 2

CUSA processing protocol. Pictures show the key passages performed starting from the CUSA material

Fig. 3

DENDR-STEM clinical study is based on GSCs as target for DC immunotherapy. The protocol for GSC derivation from CUSA material was revised according to GMP rules