Co-delivery of human cancer-testis antigens with adjuvant in protein nanoparticles induces higher cell-mediated immune responses

Abstract

Nanoparticles have attracted considerable interest as cancer vaccine delivery vehicles for inducing sufficient CD8 T cell-mediated immune responses to overcome the low immunogenicity of the tumor microenvironment. Our studies described here are the first to examine the effects of clinically-tested human cancer-testis (CT) peptide epitopes within a synthetic nanoparticle. Specifically, we focused on two significant clinical CT targets, the HLA-A2 restricted epitopes of NY-ESO-1 and MAGE-A3, using a viral-mimetic packaging strategy. Our data shows that simultaneous delivery of a NY-ESO-1 epitope (SLLMWITQV) and CpG using the E2 subunit assembly of pyruvate dehydrogenase (E2 nanoparticle), resulted in a 25-fold increase in specific IFN-γ secretion in HLA-A2 transgenic mice. This translated to a 15-fold increase in lytic activity toward target cancer cells expressing the antigen. Immunization with a MAGE-A3 epitope (FLWGPRALV) delivered with CpG in E2 nanoparticles yielded an increase in specific IFN-γ secretion and cell lysis by 6-fold and 9-fold, respectively. Furthermore, combined delivery of NY-ESO-1 and MAGE-A3 antigens in E2 nanoparticles yielded an additive effect that increased lytic activity towards cells bearing NY-ESO-1 and MAGE-A3. Our investigations demonstrate that formulation of CT antigens within a nanoparticle can significantly enhance antigen-specific cell-mediated responses, and the combination of the two antigens in a vaccine can preserve the increased individual responses that are observed for each antigen alone.

Co-encapsulation of curcumin and doxorubicin in albumin nanoparticles blocks the adaptive treatment tolerance of cancer cells

“…Pre-treatment with Erlotinib inhibited the epidermal growth factor receptor (EGFR) and increased the therapeutic efficacy of doxorubicin (Dox) in a subset of triple-negative breast cancers (Lee et al 2012). However, the sequential co-administration of drugs to cancer cells is not always the best option (Neek et al 2018). Ducreux et al have shown that the simultaneous co-administration of drugs led to more cytotoxic effects on advanced, resectable colorectal cancer compared to the sequential drug co-administration (Ducreux et al 2011).…”

Effective Activation of Human Antigen-Presenting Cells and Cytotoxic CD8+ T Cells by a Calcium Phosphate-Based Nanoparticle Vaccine Delivery System

“…Therapeutic vaccines such as CaP NPs could increase the quantity and efficacy of virus-specific cytotoxic CD8 + T cell responses to enhance the killing of latently infected cells [41,42]. With the flexible CaP NP system, it would be possible to individually prime antigen specific T cell responses against vulnerable regions of the virus, which has been effective for HIV control [43,44], but may also be important for the reinforcement of tumor-specific immune responses [45].…”

多肽药物及组装体在癌症免疫治疗中的应用

“…Gazzinelli and coworkers [129] connected antigen NY-ESO-1 and adjuvant CpG DNA to carbon nanotubes (CNT) and developed a new anti-cancer vaccine platform. Wang and coworkers [90] employed E2 viral-like capsules to simultaneously encapsulate antigens NY-ESO-1 and HLA-A2 to overcome the low immunogenicity of individual antigens. In addition, the epitopes derived from human papillomavirus (HPV) including HPV16 E7 11-20 [100,101], E7 86-93 [101], E7 43-57 [102,103,130], E7 49-57 [101,103,131], and E7 48-54 [103,104], or from oncofetal antigen including OFA 1, OFA 2, and OFA 3 [105], have been utilized as antigens for cancer immunotherapy.…”