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Finocchiaro G.,Unit of Molecular Neuro oncology | Pellegatta S.,Unit of Molecular Neuro oncology
Current Opinion in Oncology | Year: 2014

Purpose of review Avoiding immune destruction is one emerging hallmark of cancer, including glioblastoma. The number of immunotherapy approaches to fight glioblastoma is growing. Here, we review the recent progress in four main areas: dendritic cell immunotherapy, peptide vaccination, chimeric antigen receptors and immune checkpoints. Recent findings We and others are using dendritic cells to present glioblastoma antigens (whole tumor lysate) to the immune system; our initial data indicate that clinical benefit is associated to increased presence of natural killer cells in the periphery. A pilot study loading dendritic cells with glioblastoma stem-like cells will start soon. Peptide vaccination targeting the epidermal growth factor receptor variant III (EGFRvIII) epitope, present in 25% of glioblastomas, is ongoing. Intriguing results have been obtained by vaccination with three other peptides in pediatric gliomas. Another clinical trial is targeting EGFRvIII by adoptive cell transfer of chimeric antigen receptor. This exciting technology could be suited for a number of other potential epitopes discovered through next-generation sequencing. Finally, antibodies against the immune checkpoints cytotoxic T lymphocyte antigen-4 and programmed cell death-1, which demonstrated efficacy in advanced melanomas, will be used in novel trials for recurrent glioblastoma. Summary In all these studies attention to novel side-effects and to MRI as immunological follow-up to distinguish progression or pseudoprogression will be of critical relevance. Copyright © Lippincott Williams & Wilkins. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Finocchiaro G.,Unit of Molecular Neuro oncology | Pellegatta S.,Unit of Molecular Neuro oncology
Cancer Immunology, Immunotherapy | Year: 2016

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. © 2015, Springer-Verlag Berlin Heidelberg.

Finocchiaro G.,Unit of Molecular Neuro oncology | Pellegatta S.,Unit of Molecular Neuro oncology
Discovery Medicine | Year: 2015

Converging data indicate that the immune system is able to recognize cancer epitopes as non-self and mount an immune reaction that may erase, or temporarily block, tumor growth. The immune pressure supports the amplification of immune resistant tumor clones, creating an immune suppressive environment that leads to the formation of a clinically relevant tumor. These general observations also apply to brain tumors and specifically to gliomas. Cancer immunotherapy strategies are aimed at reverting such immune suppression. Two approaches are already used in the clinics. The first one, peptide immunotherapy, has been oriented to the most aggressive glioma, glioblastoma (GBM) where, in the context of EGFR (epidermal growth factor receptor) amplification, a large deletion arises and creates a novel, cancer-specific antigen, EGFRvIII. The second one is dendritic cell immunotherapy. Dendritic cells are potent antigen presenting cells that can be pulsed with autologous tumor lysate or peptide pp65 from cytomegalovirus (CMV) that is present in GBM but not in normal brain. Antigen presentation by dendritic cells is bolstered by preconditioning their injection site with the tetanus/diphtheria toxoid. The third approach is adoptive cell therapy (ACT) in which tumor-specific T cells can be amplified ex vivo and subsequently re-injected to the patient to lyse cells expressing tumor antigens, increasing survival durably in a fraction of melanoma patients. ACT may also be based on T cell transduction of tumor specific receptors or chimeric antigen receptors (CARs). CARs are powerful tools for immunotherapy but off-target toxicity may be an issue as they do not request MHC presentation for activation. Upcoming clinical trial results will clarify the most effective direction for cancer immunotherapy in gliomas and other cancers with poor prognosis. © 2015, Discovery Medicine.

Finocchiaro G.,Unit of Molecular Neuro oncology | Pellegatta S.,Unit of Molecular Neuro oncology
Current Opinion in Neurology | Year: 2011

Purpose of Review: During recent years different approaches have been explored to raise effective antitumor responses against brain tumors and particularly glioblastomas (GBMs). In most cases, cancer vaccines were based on autologous dendritic cells loaded with GBM peptides or whole tumor lysates. Many phase I-II studies showed that such strategy is feasible and nontoxic but failed to provide convincing evidence of its efficacy. This was due to study design and other biological issues: local immune suppression and insufficient characterization of appropriate epitopes appear as particularly relevant. Recent Findings: In neuro-oncology intriguing data have been obtained by vaccinating patients with the epidermal growth factor receptor variant III (EGFRvIII) peptide, reproducing a specific epitope arising because of large deletion of the EGFR gene. In other cancers immunotherapy is obtaining clinically meaningful results: in prostate cancer vaccination with dendritic cells loaded with a cancer peptide, and in metastatic melanoma antibodies against an immune gate-keeper, CTL4, both led to increased survival and have been approved by FDA. Summary: On the basis of these and other clinical and preclinical findings it appears that several approaches may have chances of clinical success. They include combinatorial treatments of chemotherapy and immunotherapy, systemic and local immunotherapy, vaccination against specific targets, for example cytomegalovirus protein or stem cell markers re-expressed during brain cancer progression. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Nava F.,Unit of Neuroepidemiology | Tramacere I.,Unit of Neuroepidemiology | Fittipaldo A.,Unit of Neuroepidemiology | Bruzzone M.G.,Unit of Neuroradiology | And 9 more authors.
Neuro-Oncology | Year: 2014

BackgroundProspective follow-up studies of large cohorts of patients with glioblastoma (GBM) are needed to assess the effectiveness of conventional treatments in clinical practice. We report GBM survival data from the Brain Cancer Register of the Fondazione Istituto Neurologico Carlo Besta (INCB) in Milan, Italy, which collected longitudinal data for all consecutive patients with GBM from 1997 to 2010.MethodsSurvival data were obtained from 764 patients (aged>16 years) with histologically confirmed primary GBM who were diagnosed and treated over a 7-year period (2004-2010) with follow-up to April 2012 (cohort II). Equivalent data from 490 GBM patients diagnosed and treated over the preceding 7 years (1997-2003) with follow-up to April 2005 (cohort I) were available for comparison. Progression-free survival (PFS) was available from 361 and 219 patients actively followed up at INCB in cohorts II and I, respectively.ResultsSurvival probabilities were 54% at 1 year, 21% at 2 years, and 11% at 3 years, respectively, in cohort II compared with 47%, 11%, and 5%, respectively, in cohort I. PFS was 22% and 12% at 1 year in cohorts II and I. Better survival and PFS in cohort II was significantly associated with introduction of the Stupp protocol into clinical practice, with adjusted hazard ratios (HRs) of 0.78 for survival and 0.73 for PFS, or a 22% relative decrease in the risk of death and a 27% relative decrease in the risk of recurrence. After recurrence, reoperation was performed in one-fifth of cohort I and in one-third of cohort II but was not effective (HR, 1.05 in cohort I and 1.02 in cohort II). Second-line chemotherapy, mainly consisting of nitrosourea-based chemotherapy, temozolomide, mitoxantrone, fotemustine, and bevacizumab, improved survival in both cohorts (HR, 0.57 in cohort I and 0.74 in cohort II). Radiosurgery was also effective (HR, 0.52 in cohort II).ConclusionsWe found a significant increase in overall survival, PFS, and survival after recurrence after 2004, likely due to improvements in surgical techniques, introduction of the Stupp protocol as a first-line treatment, and new standard protocols for second-line chemotherapy and radiosurgery after tumor recurrence. In both cohorts, reoperation after tumor recurrence did not improve survival. © 2014 © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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