Heat shock protein vaccines against glioblastoma: from bench to bedside

Abstract

Current adjuvant treatment regimens available for the treatment of glioblastoma are widely ineffective and offer a dismal prognosis. Advancements in conventional treatment strategies have only yielded modest improvements in overall survival. Immunotherapy remains a promising adjuvant in the treatment of GBM through eliciting tumor specific immune responses capable of producing sustained antitumor response while minimizing systemic toxicity. Heat shock proteins (HSP) function as intracellular chaperones and have been implicated in the activation of both innate and adaptive immune systems. Vaccines formulated from HSP-peptide complexes, derived from autologous tumor, have been applied to the field of immunotherapy for glioblastoma. The results from the phase I and II clinical trials have been promising. Here we review the role of HSP in cellular function and immunity, and its application in the treatment of glioblastoma.

Figure 1. HSP-peptide complex interaction with antigen presenting cells

The proposed mechanism by which the HSP-peptide complex interacts with APC’s consists of cell surface receptor interaction. Primarily, CD91 has been shown to endocytose the complex and via either proteasome dependent or independent pathways lead to the presentation via MHC-class I receptor. In addition, a portion of the internalized complex enters an acidic compartment which leads to its loading onto MHC-class II receptors. Additional cell surface receptors, such as TLR2/TLR4, and others that have not been elucidated are also involved in eliciting a downstream effect which leads to the activation of the NF-κB pathway. Upon activation, proinflammatory cytokines and chemokines are generated and secreted in order to further augment a proinflammatory response.