Active‐specific immunotherapy of human cancers with the heat shock protein Gp96—revisited

Abstract

The passive administration of specific antibodies that selectively target tumors is a well-known strategy in cancer treatment. Active immunotherapy using peptide vaccines, in contrast, is expected to induce specific, cytolytic T cells in the patient, which react against tumor antigens and destroy malignant cells. Although several concepts exist, the identification and low immunogenicity of tumor-specific peptides remain a serious problem. Heat shock proteins (HSPs), notably glycoprotein (Gp) 96, are of special interest, because they are able to take molecular peptide-fingerprints of the protein array characteristic for a particular cell. Association of Gp96 with peptides has been shown to be essential for crosspresentation and activation of T cells. Consequently, Gp96-peptide complexes extracted from cancer cells harbor the tumor-specific peptides and are immunogenic, thus offering a tool for active immunization against the tumor. Already, several immunotherapy studies of human cancers have been carried out, showing no severe adverse effects but unfortunately only limited improvement in the clinical outcome. Vitespen, a commercial HSP-peptide complex vaccine based on tumor-derived Gp96, seems to induce an improved overall survival for subsets of early stage melanoma and kidney cancer patients. The limited access to vaccine material derived from the autologous tumor requires the development of alternative protocols. Moreover, counteracting immunosuppressive mechanisms induced by the malignancy might further improve the efficacy of vaccinations. This review critically analyzes the current state of clinical immunotherapy with Gp96, with special attention to Vitespen.Heat shock proteins (HSPs) came to attention of immunologists, because they chaperone peptides and interact with antigen-presenting cells (APCs) in a specific manner. As molecular chaperones, HSPs are essential for maintaining cellular functions by preventing misfolding and aggregation of nascent polypeptides and by facilitating protein folding. This function has been described for every organism. 1In the 1980s, the potential importance of HSPs for tumor therapy emerged, when it was observed that preparations of certain HSPs isolated from cancer cells elicited immunity by capturing the antigenic fingerprint of a specific cancer, so that they could act as a vaccine against subsequent tumor challenge.2 Since then, the immunological properties of HSPs were studied intensively, particularly those of endoplasmic reticulum (ER)-resident HSPs glycoprotein (Gp)96 (Grp94)

Isolation and Identification of Renal Cell Carcinoma-Derived Peptides Associated with GP96

“…Consequently, gp96-peptide complexes extracted from cancer cells harbor tumor-specific peptides and are immunogenic, offering a tool for active immunization against the tumor (13)(14)(15)(16)(17). Therefore, immunologists speculate that every preparation of gp96-associated peptide pool is different.…”

Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential

“…Although vaccination of lethally irradiated cancer cells expressing autologous secretory GRP94 fusion proteins protected mice from primary tumour growth and metastasis 158 , vitespen, a GRP94-peptide complex that was purified ex vivo from individual patient's tumour cells showed variable immunogenicity and overall limited efficacy in clinical trials, with clinical responses only in certain patient subsets 159-161 . Recent studies showed that low dose of GRP94 immunization activated cytotoxic T lymphocytes with some tumour suppression in mice whereas high dose induced Treg proliferation and immune suppression, in a manner dependent on TLR-mediated NF-κB activation 162 .…”

Heat shock protein vaccination and directed IL-2 therapy amplify tumor immunity rapidly following bone marrow transplantation in mice

“…87,88 Although immune correlates were elicited, overall patient survival was relatively unchanged compared with standard of care regimens. 89 Notably, the first successful phase 1 trial using a human allogeneic lung cancer cell line engineered to secrete gp96-Ig was recently completed.…”