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Dendritic Cells Pulsed with Viral Oncolysate

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Abstract

Glioblastoma multiforme (GBM) is an aggressive malignant tumour of the central neural system (CNS). Despite an improved surgical management and treatment by radiotherapy and adjuvant chemotherapy with temozolomide (TMZ), this form of cancer shows a poor prognosis with a median survival of less than 15 months. The use of dendritic cell (DC)-based active vaccination to bolster the otherwise impaired antitumour immune responses in glioma patients has received increasing attention. Early clinical trials demonstrated the safety and immunogenicity of autologous DCs loaded exogenously with various antigens. However, such DC vaccines have unfortunately rarely translated into strong clinical effects. The main reasons appear to be limitations in the induction of strong cellular antitumour immune responses able to counteract glioma-induced immunosuppression.

This may be due (1) to the immature/intermediate state of the used DCs that may induce tolerance and (2) to the lack of danger signals and type 1 polarisation signals, which create the proper context, in which tumour antigens should be presented by DCs to T cells. In this chapter, we introduce a new DC vaccine with reduced tolerogenic and enhanced immunogenic potential. The improved vaccine (NDV-DC) combines DCs with autologous tumour cells and danger signals provided by infection with an oncolytic strain of Newcastle Disease Virus (NDV). The uniqueness of this approach is associated with three important properties of NDV as bird paramyxovirus: tumour-selective replication, oncolytic potential and immune stimulatory capacity. Glioblastoma patients will be vaccinated post-operatively by intradermal applications of the NDV-DC vaccine, which is composed of ex vivo cultured patient-derived DCs loaded with viral oncolysate from NDV-infected autologous tumour cells.

When such tumour antigen-presenting DCs are applied to patients, their tumour antigen-specific T cells will receive several activation signals: (1) The tumour antigens will provide the T-cell activation signal 1, and (2) simultaneously, NDV-DC will provide so-called danger signals of importance for the induction of signal 2 (T-cell costimulation) and signal 3 (T-cell polarisation towards Th1). Compared to classical DC vaccines, NDV-DC presents improved T-cell activation signals required for induction of CD4+ and CD8+ T-cell-mediated immune responses resulting in the stimulation of strong and systemic tumoricidal T-cell immunity.

Through its capacity to induce interferon (IFN)-α and interferon (IFN)-ß, NDV also provides a link between the innate and the adaptive immunity system, thus further strengthening the anticancer immune response. NDV-induced molecular danger signals (viral RNA and HN protein) drive DCs to become Th1-directed immunogenic antigen-presenting cells able to overcome immunosuppression and tolerance mechanisms. Such a combination of oncolytic NDV with patient’s tumour cells and autologous DCs will be evaluated initially against glioblastoma but it is applicable against virtually all types of cancer.

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The authors declared that no competing financial interests exist.

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Authors and Affiliations

  1. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Philippe Fournier PhD & Volker Schirrmacher PhD

  2. IOZK Cologne, Cologne, Germany

    Volker Schirrmacher PhD

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  1. Philippe Fournier PhD
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  2. Volker Schirrmacher PhD
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Correspondence to Volker Schirrmacher PhD .

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  1. Institute for Molecular Vaccines, Heidelberg, Germany

    Matthias Giese

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Fournier, P., Schirrmacher, V. (2013). Dendritic Cells Pulsed with Viral Oncolysate. In: Giese, M. (eds) Molecular Vaccines. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1419-3_26

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