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Reverse tolerization against glioblastoma by individualized vaccination with tumor antigen-derived designer peptides

English title Reverse tolerization against glioblastoma by individualized vaccination with tumor antigen-derived designer peptides
Applicant Martin Roland
Number 153213
Funding scheme Project funding (Div. I-III)
Research institution Neurologische Klinik Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Immunology, Immunopathology
Start/End 01.12.2014 - 31.05.2018
Approved amount 219'000.00
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Keywords (5)

tumor vaccination; Glioma; Immunotherapy; individualized cancer therapy; tumor antigen

Lay Summary (German)

Lead
Ziel des Projektes ist die Entwicklung einer individualisierten Impfung gegen das Glioblastom mit auf Tumorantigenen basierenden designten Peptiden. Für diesen Ansatz werden verschiedene experimentelle und computerbasierte Methoden benutzt.
Lay summary

Das Glioblastom ist der häufigste bösartige hirneigene Tumor bei Erwachsenen. Trotz multimodaler  Therapieansätze inklusive Chirurgie, Radiotherapie und Chemotherapie liegt die mittlere Überlebenszeit  bei ca. 15 Monaten. Daher gibt es einen dringenden Bedarf an neuen therapeutischen Strategien.  Einer dieser Ansätze ist die Immuntherapie.

Gliomzellen exprimieren tumorassoziierte Proteine.  Da Tumorzellen jedoch aus körpereigenen Zellen hervorgehen besteht gegen diese Tumorantigene eine starke Immuntoleranz.

Unser Forschungsziel ist es diese Immuntoleranz durch eine Impfung basierend auf künstlich-gefertigten Peptiden zu überwinden. Diese Peptide werden in-silico designt und in-vitro und in-vivo getestet. Dieses Konzept könnte einen neuen therapeutischen Ansatz für eine individualisierte Krebstherapie einleiten.

Direct link to Lay Summary Last update: 12.11.2014

Lay Summary (English)

Lead
The objective of this project is to establish an individualized vaccination against glioblastoma based on tumor antigen-derived designer peptides. For this purpose various experimental and computational methods will be used.
Lay summary

Glioblastoma is the most common primary malignant brain tumor in adults. Despite multimodal therapeutic approaches including maximal surgical resection and radiotherapy in combination with concomitant and adjuvant chemotherapy with temozolomide, the median survival of glioblastoma patients is in the range of only 15 months. Consequently there is an urgent need for novel treatment modalities. One of these approaches is cancer immunotherapy. Glioma cells express proteins which potentially allow for an interaction with immune cells but the ancestry from normal tissue leads to a strong immune tolerance against the gliomatous tumor.

The aim of this research is to overcome this immune tolerance by a vaccination based on artificially designed peptides. These peptides are designed in silico and are tested in vitro and in vivo. This innovative immunotherapeutic approach might result in a breakthrough in the individualized design of immunological cancer therapy.
Direct link to Lay Summary Last update: 12.11.2014

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
A tissue-based draft map of the murine MHC class I immunopeptidome
Schuster Heiko, Shao Wenguang, Weiss Tobias, Pedrioli Patrick G.A., Roth Patrick, Weller Michael, Campbell David S., Deutsch Eric W., Moritz Robert L., Planz Oliver, Rammensee Hans-Georg, Aebersold Ruedi, Caron Etienne (2018), A tissue-based draft map of the murine MHC class I immunopeptidome, in Scientific Data, 5, 180157-180157.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Hans-Georg Rammensee Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Roy Mariuzza, PhD United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. L. Regli, Dept. Neurosurgery, Univ. Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr. Björn Windshügel Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Awards

Title Year

Abstract

Glioblastoma is the most frequent and most malignant intrinsic brain tumor. It is diagnosed in the sixth decade of life most often, but may affect all age groups including children. Despite modest advances in therapy, still more than half of the patients die from their cancer within the first year. This is because these tumors infiltrate the healthy brain tissue, precluding complete surgical resection, and because the tumor cells are rather resistant to radiotherapy and chemotherapy. Thus, innovative treatment approaches for glioblastoma are urgently needed. Among these immunotherapy receives particular attention, also because glioblastomas are paradigmatic for cancer-associated immunosuppression. The first phase III trial of vaccination for newly diagnosed patients with glioblastoma, ACT IV, is currently enrolling patients and was co-designed by the co-applicant MW. Yet, trial participation is restricted to only about 20-25% of glioblastoma patients whose tumors carry a specific mutation of the epidermal growth factor receptor (EGFR) gene referred to as EGFRvIII.Tumor-associated antigens are by definition self-proteins, hence immunologic tolerance of these is strong. Moreover, tumors have developed further active mechanisms to maintain immune privilege including the release of the master immunosuppressive molecule, transforming growth factor (TGF)-ß. Consequently, it is difficult to induce tumor-specific immune responses against glioblastoma cells. One promising way to overcome this problem is to employ artificially designed peptides, which are based on a tumor antigen, i.e., ideally a protein that is relatively specifically expressed in the tumor, but not in other vulnerable tissues. These tumor antigen-derived designer (TADD) peptides are derived from a tumor-associated self-protein, bind to the patient’s HLA-class I- or class II peptides and are altered in T cell receptor (TCR) contact positions to overcome stringent tolerance against the native self-protein. As prior data from our laboratories have shown, some of the variant peptide-responsive T cell clones respond to the native peptide, too, and even much more efficiently and at much lower concentrations. These data documented that robust immune tolerance against self-proteins that are expressed in the thymus can be overcome by vaccination with variant peptides, i.e. reverse tolerance was achieved.Rather than relying on naturally occurring mutations in glioblastoma, we propose here to rationally design TADD peptides. Suitable tumor proteins fall into one of the following categories: naturally occurring mutations of self-proteins (category 1), developmentally expressed tumor antigens (category 2), proteins/peptides expressed in tumor lineage-specific context (category 3), or proteins known to be expressed/over-expressed in glioblastoma (category 4). Category 1-3 peptides will be identified as part of this proposal by mouse and human tumor peptidome- and transcriptome analysis, and initial vaccination attempts in a small number of glioblastoma patients will be based on pre-determined category 4 peptides. By combining TADD peptides for CD4+ and CD8+ peptides, we aim at simultaneously stimulating both helper and effector T cells to induce effective and specific anti-glioma immunity. A distinct advantage of TADD peptides over mutated peptides that naturally occur in the tumor is the low frequency of the latter and the fact that these are often not processed and presented. To establish proof-of-concept we will explore this strategy in rodent glioma models in vitro and in vivo as well as in human in vitro models; in addition, a small number of individual treatment attempts in glioblastoma patients is planned. This proposal is meant to lay the foundation for future efforts to translate this approach into a phase I/IIa first-in-man clinical trial that shall document the tolerability and safety as well as provide evidence for the induction of efficient anti-tumor response by ex vivo immunomonitoring studies. The clinical trial shall not be pursued within the scope of the present application.
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