The immunological era in melanoma treatment: new challenges for heat shock protein-based vaccine in the advanced disease

Introduction: Tumor-derived heat shock protein (HSP)–peptide complexes (HSPPCs) induced immunity against malignancies in preclinical trials, working across tumor types and bypassing the need to identify single immunogenic peptides. These results paved the way for the use of human gp96 obtained from autologous tumor samples as an anti-cancer vaccine.

Areas covered: Autologous tumor-derived HSP gp96 peptide complex (HSPPC-96) vaccine is emerging as a tumor- and patient-specific cancer vaccine, with confirmed activity in several malignancies. It has been tested in Phase III clinical trials in advanced melanoma and kidney cancer with evidence for efficacy in patients with earlier stage disease. HSPPC-96-based vaccine demonstrated an excellent safety profile, thus emerging as a novel therapeutic approach with a suggestive role in cancer therapy. This review summarizes work on the use of HSPPC-96 as an autologous anti-tumor vaccine in advanced melanoma. Data were retrieved by PubMed and Medline research and using the authors' personal experience.

Expert opinion: Further investigations are needed to understand the biological basis of immune functions in order to improve the clinical outcome of HSP-based cancer therapy. In the near future, the combination of HSP-based vaccines with other biological compounds might represent a successful strategy in the therapy of advanced melanoma.     

HSP类自体肿瘤疫苗Vitespen

热休克蛋白（heat shock proteins,HSPs）为一类高度保守的应激诱导蛋白,其功能是作为分子伴侣在不同的细胞腔隙中运输多肽和释放由主要组织相容性复合物（MHC）Ⅰ类分子递呈的肽类如免疫原性肽。在HSPs家族中,葡萄糖调节蛋白GRP94（即糖蛋白gp96）及HSP-90、-70、-110和GRP170已在肿瘤组织中被发现并被分离出,它们可诱发抗肿瘤的细胞免疫,但其本身并无免疫原性,只是作为抗原肽类的一种载体或分子伴侣,形成一种源于肿瘤的HSP-肽复合物（HSPPCs）,方能引发对肿瘤的特异性免疫作用。     

Treating human cancers with heat shock protein-peptide complexes: the road ahead

Background: Heat shock proteins (HSPs) chaperone a wide array of peptides generated in cells. Association of HSPs with peptides is critical for loading of MHC I with epitopes, and has been suggested to be essential for cross-presentation. HSP–peptide complexes purified from cancer cells have been shown to chaperone tumor-specific antigenic epitopes, and have been used in experimental immunotherapy of human cancers. Two randomized Phase III trials have been completed recently. Objective: To summarize the lessons learned from the Phase III studies and to opine on the path forward. Results/conclusion: Immunization of human subjects with HSP–peptide complexes derived from autologous tumors mediates substantial clinical benefit in subjects with relatively early stage disease, consistent with results seen in animal models of cancer, and with an immunological mechanism of action. Additional clinical studies are essential for further development of this personalized medicine.