Neoantigen Vaccination

Neoantigen peptide vaccination has recently been emerging as a promising immunotherapy for cancers. The peptide vaccine can induce T cell response relying on the specificity of the T cell receptor to recognize a presented oligopeptide-epitope.

What is neoantigen?

The development and function of an organism is largely controlled by genes. Gene mutations can lead to changes in the structure of an encoded protein and subsequently the protein function. Expression of non-synonymous mutations can produce tumor-specific antigens called neoantigen. Neoantigen are immunogenic as they are not expressed in normal tissues. They can activate CD4+ and CD8+ T cells to generate immune response and have the potential to become new targets of tumor immunotherapy.

How is neoantigen peptide vaccine designed?

After the whole-exome sequencing, different bioinformatics algorithms are used to identify and predict the affinity of neoantigen to major histocompatibility complexes (MHCs). One of the tumor vaccine targeting neoantigens is synthetic peptide vaccine. Currently hundreds of clinical trials have demonstrated the safety and efficacy of peptide vaccines.

Figure 1. Mutations in tumor tissue produce neoantigens. Tumor tissue DNA sequences can be compared to normal tissue ones and use bioinformatics software to predict and prioritize the immunogenicity of neoantigens. (Peng M, et al. Mol Cancer, 2019, 18:128)

How does it work?

Cancer cells expressing neoantigens can be distinguished from normal cells by the immune system in the same way that bacteria or virus-infected cells are identified. Recognition of an unusual antigen starts an immune response aimed at elimination of the cell and generation of antigen-specific immune cells that provide long-lasting immunity. However, immune-mediated regression of cancer hardly ever takes place in real life due to the low effectiveness of wild-type antigens (generated by the tumor) in stimulating host immune responses.

Neoantigen peptide vaccine therapy is a means to provide a highly immunogenic antigen/peptides, which are capable of stimulating the immune system to mount a cytotoxic attack against the tumor cells. The desired effect would be stabilization or even regression of the disease. The mechanism is illustrated as Figure 2.

Figure 2. The mechanism of anti-cancer effect of peptide vaccine therapy: Peptide vaccine can be inoculated near lymph nodes and processed and presented by the antigen-presenting cells (APCs) in lymph nodes resulting in activation of CD4+ helper T cells and CD8+ Cytotoxic T cells to kill tumor cells. (Bartnik A, et al. Vaccine 2013, 1:1-16)

What assay can be used to monitor the vaccine effect?

Peptide vaccine immunotherapy is a therapy that induces cellular immune responses against a target molecule (neoantigen peptide) to elicit clinical anti-tumor effects. These cellular immune responses against the target molecule are monitored to evaluate whether the antigen-specific cellular immune responses are induced and maintained during the vaccination period. Enzyme-linked immunospot (ELISPOT) assay is widely performed to analyze not only the frequency of immune cells, but also their effector functions as determined by their cytokine production/secretion.

The ELISPOT assay is highly quantitative, can measure a broad range of magnitudes of response and is capable of assessing critical cellular immune-related activities such as IFN-γ secretion and granzyme B release. Furthermore, ELISPOT is adaptable not only to the evaluation of a variety of T-cell functions, but also to B cells and innate immune cells. It is no wonder that ELISPOT has evolved from a research tool to a clinical assay.

Recent Phase I and II studies of cancer vaccines, tested in a variety of malignancies, have suggested that ELISPOT may be a useful biomarker assay to predict clinical benefit after therapeutic immune modulation.

Written By: Feng Lin, M.D., Ph.D.

Keywords: Elispot, Granzyme B, Neoantigens, Epitope