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

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

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Abbreviations

b-FGF:

Basic-fibroblast growth factor

CSCs:

Cancer stem cells

CUSA:

Cavitation ultrasonics surgical aspirator

DCs:

Dendritic cells

EGF:

Epidermal growth factor

GBM:

Glioblastoma

GMP:

Good manufacturing practice

GSCs:

Glioblastoma stem-like cells

HIF-1α:

Hypoxia-inducible factor-1α

IFN-γ:

Interferon-γ

NK:

Natural killer

NS:

Neurospheres

OS:

Overall survival

PBMCs:

Peripheral blood mononuclear cells

PFS:

Progression-free survival

TAA:

Tumor-associated antigen

TGF-β:

Transforming growth factor

TMZ:

Temozolomide

TNF-α:

Tumor necrosis factor-alpha

VEGF:

Vascular endothelial growth factor

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Acknowledgments

We thank the colleagues from the Department of Neurosurgery of the Istituto Besta, Dr Bianca Pollo and the colleagues of the Unit of Neuropathology, the staff of the cell factory (Cell Therapy Production Unit—UPTC), the Besta Brain Tumor Biobank (BBTB), Mr Piero Tieni (SOL Group Spa, Italy) for the cryo-management service and the technical assistance, Dr Lucia Cuppini for clinical data-management, and Drs Paola Porrati and Elisa Bottega for help in developing the GLP protocol for GSCs generation from CUSA bags. We thank the patients participating in the clinical studies and their families. DENDR-STEM clinical study is supported by Ministry of Health to G. Finocchiaro (RF-2010-2316156), and AIRC (Associazione Italiana per la ricerca sul cancro) (IG 2012 13043) to G. Finocchiaro. DENDR1 and DENDR2 are sponsored by Istituto Besta. DENDR1 is a study carried out as part of an oncology network (Rete Oncologica Lombarda) and funded referring to the deliberations of the regional council of Regione Lombardia no VIII/010761 of 11-12-2009 and DGR IX/1485 of 30-03-2011. Our preclinical studies have been supported by AIRC to S. Pellegatta (IG 2013 N. 14323), “il Fondo di Gio” and “Associazione Italiana Tumori Cerebrali” (AITC).

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  1. Unit of Molecular Neuro-Oncology, Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Via Celoria 11, 20133, Milan, Italy

    Gaetano Finocchiaro & Serena Pellegatta

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  1. Gaetano Finocchiaro
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Correspondence to Gaetano Finocchiaro or Serena Pellegatta.

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Part of our data were reported in the abstract book of the conference “11th Congress of the European Association of Neuro-Oncology, Turin, Italy, October 9–12, 2014.”

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Finocchiaro, G., Pellegatta, S. Immunotherapy with dendritic cells loaded with glioblastoma stem cells: from preclinical to clinical studies. Cancer Immunol Immunother 65, 101–109 (2016). https://doi.org/10.1007/s00262-015-1754-9

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