​Six tumor vaccines and their advantages and disadvantages

DNA vaccine DNA vaccine uses plasmid DNA to encode the antigen sequence.

Through intramuscular injection or subcutaneous injection of plasmid DNA, combined with electroporation to transduce the cells at the injection site, the antigen is transcribed and translated, which is then taken up by antigen presenting cells (APC), and presented to CD8+ T cells and CD8+ T cells through MHC class I molecules and MHC class II molecules.
CD4+ T cells, in turn, activate T cells, make them proliferate and differentiate, become effector T cells, and ultimately produce anti-tumor immunity.

The working principle of DNA vaccines (Document 1) The basic structure of mRNA used in mRNA vaccine therapy (Document 2) The mRNA vaccine directly enters the cell through the plasma membrane (such as electroporation).

mRNA does not enter the nucleus, nor does it integrate into the genome (this is different from DNA vaccines).

Translation takes place in the cytoplasm, and there is no difference between the protein translated from synthetic mRNA and the protein translated from endogenous mRNA.

The protein is post-translationally modified and enters the subcellular compartments (secretory pathway, cell membrane, nucleus, mitochondria or peroxisomes) through targeting sequences or transmembrane domains.

Eventually, the protein is taken up and degraded by APC, and presented to T cells on the major histocompatibility (MHC) complex to activate anti-tumor immunity.

Long peptide vaccines Originally, peptide-based cancer vaccines were usually composed of short peptides bound to precise MHC-I.

Although these vaccines produced a strong T cell response, when they used mineral oil adjuvant, Montanide ISA-51 VG and TLR9 ligand, CpG 7909, the T cell response was poor.

Short peptides bind to MHC-I molecules on all cells expressing MHC-I molecules (all nucleated cells), while only DCs express the costimulatory molecules required for proper T cell responses.

In the mouse model, short peptide antigens can present antigens throughout the body without proper co-stimulation, causing the aggregation of CD4+ T cells, but because there are no costimulatory molecules, many cells die.

In contrast, long peptide vaccination only resulted in DCs focusing and antigen presentation in the lymph nodes drained by the vaccine, and activation of CD4+ T cells, which in turn assisted the activation of CD8+ T cell effector cells and the formation of memory T cells.

Therefore, tumor vaccines now use long peptides.

Viral vector vaccines and bacterial vector vaccines Viral vectors and bacterial vectors (Document 3) viruses have natural immunogenicity, and their genetic material can be engineered to contain sequences encoding tumor antigens.

Several recombinant viruses (such as adenovirus) can be used as vectors to infect immune cells, such as antigen presenting cells (APCs), especially dendritic cells (DCs).

Therefore, a large number of tumor antigens are presented in the immune system, and APCs such as DCs activate T cells to produce anti-tumor immunity.

Moreover, if an oncolytic virus is used as a carrier, the virus itself can also lyse tumors, release tumor antigens, further increase the effectiveness of the vaccine, and can produce long-term immune memory.

As early as 100 years ago, Busch and Fehleisen et al.
first reported the connection between cancer and bacteria, in which Streptococcus pyogenes infection led to tumor regression.

Later William Bradley Coley, also known as the father of immunotherapy.

He found 47 cases of tumor regression after acute bacterial infection.

In 1891, he tried to use a mixture of live or inactivated Streptococcus pyogenes to stimulate the immune system of cancer patients and treat bone tumors.
This should be the first tumor immunotherapy case, and it has been 130 years.

Using bacteria as a carrier to deliver therapeutically important transgenes has many advantages.

For example, Bacillus is highly active and active under common anaerobic/hypoxic conditions (the tumor microenvironment is mostly a hypoxic environment).

Some auxiliary nutrient strains, for example, Salmonella are attracted to the tumor microenvironment and absorb and metabolize nutrients.

Because of these advantages, and because of their high metabolic activity in tumor cells, they are considered as potential candidates for providing anti-cancer tumor drugs/gene vaccines because they can enter tumors in remote areas and are not sensitive to chemotherapeutics.

DC vaccine dendritic cells (dendritic cells, DC), as a professional APC, provide the first, second, and third signals for T cell activation.

DC vaccines carrying tumor antigens are an important branch of tumor vaccines.

DCs cells loaded with tumor antigens can directly activate T cells, cause cell activation, and produce anti-tumor immunity.

In order to improve the efficacy of DC vaccines, some new strategies have been used in recent years, such as using natural DCs cells (or even sorting specific DC cell subgroups) to replace traditional monocytes to induce DC cells; tumor-associated antigen peptides are more specific Replacement of tumor neoantigen peptides; and then combined therapy to induce immunogenic cell death.

The development of DC vaccines (Reference 4) Xiaobian summary Tumor vaccines have attracted widespread attention in recent years.
In addition to mRNA vaccines that have received much attention, there are also classic DC cell vaccines, as well as DNA vaccines, long peptide vaccines, viral vector vaccines, and bacterial vector vaccines.
In various forms, they have their own advantages and disadvantages.

It not only provides flexibility of choice for development, but also challenges the selection of suitable vaccine forms.

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