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

Abstract

The immune system is a powerful resource for the eradication of cancer, but to overcome the low immunogenicity of tumor cells, a sufficiently strong CD8+ T cell-mediated adaptive immune response is required. Nanoparticulate biomaterials represent a potentially effective delivery system for cancer vaccines, as they can be designed to mimic viruses, which are potent inducers of cellular immunity. We have been exploring the non-viral pyruvate dehydrogenase E2 protein nanoparticle as a biomimetic platform for cancer vaccine delivery. Simultaneous conjugation of a melanoma-associated gp100 epitope and CpG to the E2 nanoparticle (CpG-gp-E2) yielded an antigen-specific increase in the CD8+ T cell proliferation index and IFN-γ secretion by 1.5-fold and 5-fold, respectively, compared to an unbound peptide and CpG formulation. Remarkably, a single nanoparticle immunization resulted in a 120-fold increase in the frequency of melanoma epitope-specific CD8+ T cells in draining lymph nodes and a 30-fold increase in the spleen, relative to free peptide with free CpG. Furthermore, in the very aggressive B16 melanoma murine tumor model, prophylactic immunization with CpG-gp-E2 delayed the onset of tumor growth by approximately 5.5 days and increased animal survival time by approximately 40%, compared to PBS-treated animals. These results show that by combining optimal particle size and simultaneous co-delivery of molecular vaccine components, antigen-specific anti-tumor immune responses can be significantly increased.

Fluorescent nanodiamonds engage innate immune effector cells: A potential vehicle for targeted anti-tumor immunotherapy

“…45–47 Moreover, it has been shown that nanoparticles are engulfed preferentially by phagocytic myeloid cells and may serve as a mechanism to target these cells and promote a tumor-suppressive environment. 48,49 For example, in a study by Huang et al , a galactosylated cationic dextran nanoparticle-driven nucleic acid delivery system carrying CpG, anti-IL-10, and anti-IL-10 receptor oligodeoxynucleotides was utilized to target tumor-associated macrophages (TAM) to suppress their pro-tumorigenic functions and promote anti-tumor activity.…”

Display of DNA on Nanoparticles for Targeting Antigen Presenting Cells

“…11–16 We have shown that E2 possesses the capability to simultaneously deliver tumor antigens and CpG to DCs for enhanced activation of antigen-specific CD8+ T cells, yielding enhanced anti-cancer activity and increased survival time of syngeneic tumor-bearing mice. 12, 14 …”

Advancements in prophylactic and therapeutic nanovaccines

“…Immunization of mice with protein nanoparticles conjugated to melanoma-associated epitope gp100 and CpG adjuvant enhanced the production of melanoma-specific CD8 + T cells. Pre-immunization with nanoparticles delayed onset of tumor growth and increased the survival rate to 40%, showing prophylactic potential of protein nanoparticles [59] . Luo et al, showed strong cytotoxic T cell response by a physical mixture of PC7A polymeric nanoparticle and OVA antigen.…”

“…Cages like 25 nm E2 cage derived from the pyruvate dehydrogenase complex of Bacillus stearothermophilus [59] , 13 nm cage of human heavy chain ferritin (an iron storage protein) [60] , ~24 nm encapsulins (class of icosahedral cage structures) of bacteria and archaea are used for the presentation of different antigens to elicit immune response after immunization [61] . A recent study on nonviral E2 protein-based biomimetic nanoparticle-containing acidlabile CpG (DC activating molecule) and SIINFEKL peptide epitope conjugate has shown the potential to enhance the CpG mediated DC activation by 25-fold in vitro as compared to unbound CpG.…”