The novel complex combination of alum, CpG ODN and HH2 as adjuvant in cancer vaccine effectively suppresses tumor growth in vivo

Abstract

Single-component adjuvant is prone to eliciting a specific type of Th1 or Th2 response. So, the development of combinatorial adjuvants inducing a robust mixed Th1/Th2 response is a promising vaccination strategy against cancer. Here, we describe a novel combination of aluminum salts (alum), CpG oligodeoxynucleotide (CpG) and innate defense regulator peptide HH2 for improving anti-tumor immune responses. The CpG-HH2 complex significantly enhanced the production of IFN-γ, TNF-α and IL-1β, promoted the uptake of antigen and strengthened the activation of p38, Erk1/2 and NF-κB in vitro, compared to CpG or HH2 alone. Immunization with NY-ESO-1 antigen plus alum-CpG-HH2 combinatorial adjuvant effectively inhibited tumor growth and reduced tumor burden in prophylactic and therapeutic tumor models and even in passive serum or cellular therapy. In addition, co-administration of NY-ESO-1 with alum-CpG-HH2 combinatorial adjuvant markedly activated NK cell cytotoxicity, induced antibody-dependent cellular cytotoxicity (ADCC), dramatically elicited cytotoxic T lymphocytes (CTLs) response, and increased infiltrating lymphocytes in tumors. Moreover, in vivo depletion of CD8+ T cells completely and depletion of NK cells partially blocked the anti-tumor activity of NY-ESO-1-alum-CpG-HH2 immunization. Overall, our results demonstrate a novel adjuvant combination for cancer vaccine with efficient immunomodulation by stimulating innate immunity and mediating adaptive immunity.

Cellular vaccination of MLH1−/− mice – an immunotherapeutic proof of concept study

“…Confirmed by flow cytometric phenotyping, a mixture of highly activated, efficiently target cell killing NK cells and cytotoxic T cells attack MLH1 ¡/¡ tumor targets; the latter in an MHC-I restricted manner. 32,33 Another interesting finding of this study was the increased mutational load in selected MSI-target genes from vaccinated tumors, which likely constitutes some kind of escape mechanism by triggering antigenic drift. Together with the missing activation of T helper cells and upregulation of immune-checkpoint molecules this best explains final disease progression and treatment failure.…”

<p>NY-ESO-1 Protein Vaccine Combining Alum, CpG ODN, and HH2 Complex Adjuvant Induces Protective and Therapeutic Anti-Tumor Responses in Murine Multiple Myeloma</p>

“…These results suggest that NACH vaccine can significantly induce humoral immunity against multiple myeloma. Tian et al's 31 findings also suggest that vaccine combined with Alum-CpG-HH2 combinational adjuvant significantly increases the concentration of IgG in the blood of mice.…”

“…29,30,32 A previous study indicated that alum-CpG ODN-HH2 complex was an effective and novel immune adjuvant. 31 In our current study, we develop a complex vaccine based on NY-ESO-1-alum-CpG ODN-HH2 (named NACH) and examine its anti-tumor effects and immunogenicity on prophylactic and therapeutic models of murine multiple myeloma. We found that alum, CpG ODN, and HH2 complex as novel immune adjuvant combined cancer vaccine could improved the immunity efficient in murine multiple myeloma model.…”

Nanoparticles to Improve the Efficacy of Peptide-Based Cancer Vaccines

“…Iron oxide nanoparticles can also be used as potent carriers for vaccine delivery and can be used as antitumor agents for cancer therapy. A very recent study described a superparamagnetic Fe 3 O 4 as a delivery system of OVA, showing superior induction of both immune cell activation and cytokine production with effective control of tumor growth [59]. Indeed, magnetic nanoparticles can be directly controlled by an external magnetic field to significantly improve lymph node as well as intra-tumor retention [60].…”