Heat Shock Proteins (HSPs) Based Anti-Cancer Vaccines

Abstract

The importance of HSPs themselves in antigen presentation and cross-presentation remains controversial. Most studies agree that as part of their molecular chaperone function, HSPs can bind and present tumor associated antigens to professional antigen presenting cells through MHC class I and class II molecules, leading to the activation of anti-tumor CD8+ and CD4+ T cells. The regulation of the innate and adaptive immune responses by HSPs is still a matter of intense research. HSPs are seen as important anticancer vaccine adjuvants. They are used through different delivery systems: HSPs/antibodies, peptide/protein-HSP complexes, tumor antigen/HSP gene fusion, viral peptides/HSP complexes or gene fusion, viral proteins/bacterial HSP fusion. In preclinical models different administration routes, subcutaneous, intradermal, intramuscular or even peroral (under special conditions) can be used, and the animal toxicities are non-significant. The HSP-based vaccines can induce specific and non-specific cellular immune responses all of which are important to induce tumor rejection. In addition, the antibodies generated after vaccination are emerging as important protagonist in the antitumoral response. This response is significantly enhanced when the suppressive tumor microenvironment and the immune suppressing effector cells are blocked. Several clinical studies have been carried out and are ongoing, immunizing cancer patients with autologous tumor derived HSP-peptide complexes (HSPPCs). The most promising results have been observed in patients with melanoma and renal clear cell cancer without advanced disease. There are clinical trials with HSP-based anticancer vaccines other than with HSPPCs (including patients with non-Hodgkin lymphoma, high-grade transitional cell carcinoma of the bladder, high-grade cervical dysplasia, etc).

Viral-mimicking protein nanoparticle vaccine for eliciting anti-tumor responses

“…In cancer therapy, Qβ VLPs have been undergoing clinical trials for vaccination against the Melan-A/MART1 melanoma-associated tumor antigen [23]. Autologous tumor-derived heat shock proteins, hypothesized to bind autologous TAAs, have been explored for cancer vaccination as well, supporting clinical interest in natural protein-derived nanoassemblies that carry antigens [24,25]. …”

Trial Watch: Peptide-based anticancer vaccines

“…Of these studies, 13 rely on one or more TAA-derived short peptides injected as such (NCT01949688; NCT01949701; NCT01950156; NCT01961115; NCT01970358; NCT01989559; NCT01989572; NCT02019524; NCT02077114; NCT02126579; NCT02134925; NCT02149225; NCT02193347), 2 on TAA-derived short peptides encapsulated within liposomes (NCT01978964; NCT02065973), 1 on an SLP (NCT02128126), 1 on a CMP (NCT02229084), 1 on a full length, recombinant TAA (NCT02015416), and one on purified TAAs complexed with heat shock protein 90kDa b (Grp94), member 1 (HSP90B1, best known as gp96) [190][191][192][193][194] (NCT02122822) ( Table 1).…”

Pathology-Dependent Effects Linked to Small Heat Shock Proteins Expression: An Update

“…Moreover, stimulation of both innate and adaptive forms of antitumor immune responses can be achieved through tumor-derived extracellular Hsp70-, Hsp90-, and gp96-peptide complexes that bind receptors on antigen presenting cells (APCs) and deliver tumor-specific antigens to major histocompatibility complex (MHC) class I molecules on the surface of such cells [207, 226–228]. Such antigen cross-presentation interactions form the basis for the “Hsp-based anticancer vaccines technology” [174, 229, 230] whose potency depends on the ability of Hsps to chaperone tumor antigenic peptides that stimulate antitumor immune responses through Hsp receptors [226, 231, 232]. …”