[64] Examples of

hsp-based therapeutics in cancer trials are detailed in Table 3. To date, one hsp vaccine, Vitespen, is licensed and marketed. The hsp gp96, the master chaperone for Toll-like receptors[65], is the major component of Vitespen. Chaperoning by gp96 selleck compound increases uptake over unchaperoned peptides in vitro by two orders of magnitude and immunization of mice with 5 ng gp96–peptide complexes, results in generation of a peptide-specific CD4+ T-cell response.[66] In April 2008, Vitespen was approved in Russia as a patient-specific adjuvant treatment of kidney cancer for individuals at intermediate-risk for disease recurrence. Outside Russia, Vitespen is an investigational vaccine designed to treat cancer with the intent of minimizing side-effects. It has been studied extensively in clinical trials in Phase I and II settings, demonstrating efficacy in some but not all trials. Phase III studies have been

completed in which over 1300 patients with renal cell carcinoma or malignant melanoma have been treated. Essentially neither toxicity nor autoimmunity induced by Vitespen was observed.[67] Marketed (Russia) Disease-dependent Phase II and III Although pre-clinical studies with Vitespen were promising, check details clinical studies show limited efficacy.[68] This outcome may be a consequence of differences in the hsp content of Vitespen used for Phosphoglycerate kinase initial in vivo models compared with the vaccine used for clinical trials.[69] Pre-clinical studies reported utilised vaccines containing gp96 or hsp70, while clinical studies utilised vaccine containing only gp96. Critically, gp96 and hsp70 have distinct functions as endoplasmic reticulum (ER) luminal and cytoplasmic chaperones, respectively, and thus bind distinct client proteins. Heat-shock protein 70 binds a variety of cytoplasmic proteins and isolation of this hsp from tumour cells will result in the purification of intact hsp–client protein complexes. In contrast, gp96 binds membrane proteins such as

integrins and Toll-like receptors and is essential for chaperoning peptides in the ER.[70] As the clinical production processes used do not contain detergents,[71] peptides bound to gp96 in Vitespen are unlikely to result from tumour client proteins. Hence differences between the bound peptides in gp96 isolated from the homogeneous tumour tissue in the animal models and the heterogeneous tumour tissue from patients in the clinical trials may also account for the limited efficacy reported for Vitespen.[68] Other key issues concerning the future development of such a vaccine are the correct and effective dose of hsp, and which patients to target. Other hsp provide alternatives to gp96 for cancer vaccine development. Vaccination with hsp70 derived from the Meth A sarcoma, established dose-dependent immunity to challenge with Meth A sarcoma in mice.