The current situation and development trend of cancer vaccine

The cancer vaccine uses the patient’s own tumor cells, tumor-specific antigens and other immune-regulatory cells to treat and prevent cancer. The difference between the cancer vaccine and the mechanism of action of the pathogenic vaccine is that the former mainly achieves therapeutic purposes by stimulating the body’s specific immune response to cancer antigens. Thecancer vaccine is mainly obtained from the host and most macromolecules, is a normal autoantigen present in normal cells, has the specificity of the immune system, and can accurately identify cancer cell antigens from the host cells. The development of cancer vaccines is based on the premise that tumor cells are fundamentally different from normal cells, and that the immune system is able to identify and impart (by immunization), these distinctions to the goal of identifying malignant cells and regulating tumor rejection.

1. Pancreatic cancer vaccine

Pancreatic cancer is the fourth most common malignant tumor in developed countries, with a 5-year survival rate of only 7%. Due to the special anatomical location and physiological characteristics of pancreatic cancer, the onset of pancreatic cancer is insidious, there is no obvious symptoms in the early stage of the disease, the diagnosis is difficult, and it is highly invasive, so the mortality rate is very high.Diagnosis of pancreatic cancer can detect cancer antigen 19-9 levels. Cancer antigen 19-9 can be used as pancreatic cancer. An auxiliary diagnostic indicator for malignant tumors such as gallbladder cancer. In the embryonic stage, the pancreas, gallbladder, liver, intestine and other tissues have such antigens, and the normal human tissue content is very low; in the digestive tract malignant tumors, especially in the serum of patients with gallbladder cancer and pancreatic cancer, the content of cancer antigen 19-9 is significantly increased. However, the early diagnosis is of little value, mainly as a monitoring indicator and an indicator of recurrence. In addition, differential diagnosis of digestive tract diseases (such as pancreatic cancer and pancreatitis, gastric cancer and gastric ulcer) also has certain value.

Pancreatic cancer is highly immunosuppressive, and tumor-associated reactive T cell infiltration in the microenvironment is associated with a good prognosis for pancreatic cancer. Studies have shown that pancreatic cancer has multiple mechanisms to evade surveillance by the immune system, such as recruitment of negative regulatory T cells, secretion of transforming growth factor beta (TGF-beta) and interleukin 10 to suppress the immune response of the immune system, and down-regulation Expression of major histocompatibility complex I (MHC I), and the like. Recent studies have shown that necrotic apoptosis in pancreatic cancer induces chemokine ligand and macrophage-induced C-type lectin receptor signaling, promotes macrophage-induced adaptive immunosuppression, and accelerates pancreatic cancer progression.

Breaking through the immunosuppression of pancreatic cancer, enhancing the recognition of tumor-associated antigen (TAA) and activation of tumor-specific T cell responses are the core issues in the treatment of pancreatic cancer tumor vaccines. In recent years, with the development of omics, more and more relatively specific TAAs have been discovered. For example, exon sequencing can be specifically focused on a certain gene coding part, so most of the oncogene changes can be identified.There are an average of 63 genes in pancreatic cancer. These genes are mainly concentrated in 12 core signaling pathways such as Kras signal, TGF-β signal, SHH signaling pathway, etc. These changes are important for tumor tissue growth and differentiation, suggesting pancreas Cancer is the result of multiple gene mutations, and it also provides a basis for the target of pancreatic cancer tumor vaccines.The pancreatic cancer genotypes are divided into four subtypes: squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine (ADEX). The immunogenic gene program is associated with B cell signaling pathway, antigen presentation, CD4+ T cells, CD8+ T cells, and Toll-like receptor signaling pathways, and its acquired immune signaling pathways such as CTLA-4 and PD1 are up-regulated, indicating specificity. There may be breakthroughs in the study of tumor vaccines for immunogenic genotypes, suggesting that the treatment of pancreatic cancer needs to be personalized and precise.

1.2. Pancreatic cancer vaccine type

1.2.1. Peptide/gene vaccine

1.2.1.1. KRAS peptide vaccine

The KRAS gene belongs to a member of the Ras gene family and plays an important role in regulating cell proliferation and differentiation. More than 90% of pancreatic cancers have KRAS mutations and are among the earliest genetic alterations in precancerous lesions. When the KRAS gene is mutated, the conformational change of the Ras protein promotes invasion and metastasis of pancreatic cancer through its downstream RAF/MEK/ERK protein kinase cascade.

1.2.1.2. Telomerase vaccine

Telomerase maintains chromosome stability and plays an important role in cell senescence and carcinogenesis. When telomerase is activated, tumor cells are prevented from telomere-mediated cell death. Telomerase is a key molecule in inducing cell carcinogenesis. In general, telomerase is activated in more than 85% of tumor cells.

1.2.1.3. Vascular endothelial growth factor receptor 2 protein vaccine

Vascular endothelial growth factor (VEGF) signaling pathway plays a crucial role in tumor angiogenesis, in which VEGF receptor 2 (VEGFR2) mediates vascular endothelial proliferation and chemotaxis. Cells, which increase the permeability of blood vessels, are the main functional receptors of VEGF. In pancreatic cancer, VEGF/VEGFR2 is closely related to tumor growth and infiltration by regulating angiogenesis.

1.2.1.4. Mucin vaccine

Mucin1 (MUC1) is a high molecular weight type I transmembrane glycoprotein, which is normally expressed in the proximal luminal or glandular surface of epithelial cells in various tissues and organs, but in 90% of patients with pancreatic cancer. Overexpression. MUC1 interferes with cell-cell and cell-matrix linkages and plays a role in tumor signal transduction, invasion, and distant metastasis.

1.2.1.5. WT1 epitope peptide vaccine

Wilm’s tumor protein, (WT1) is a type of TAA, which is expressed in solid tumors such as lung cancer, breast cancer, thyroid cancer, and pancreatic cancer, in addition to high expression in various types of leukemia.

1.2 .2. Cell vaccine

1.2.2.1. Tumor cell vaccine

Injection of a radiation-irradiated tumor cell culture vaccine is the most primitive tumor vaccine, which utilizes all relevant tumor antigen expression expressed by tumor cells to produce a specific anti-tumor immune response. GVAX is an allogeneic whole-cell vaccine derived from two tumor cells and genetically engineered to express granulocyte colony-stimulating factor (GM-CSF). Α-galactosyl (α-GAL) is not synthesized in normal human cells, and serum contains a large amount of anti-α-GAL antibody, but tumor cells can synthesize α-GAL, so α-GAL can be used as an antigen. Induction of an anti-tumor response. Algenpantucel-L is an allogeneic tumor vaccine produced by NEWLink, which is produced using two human pancreatic ductal cancer cells genetically modified to express α-GAL.

1.2.2.2. Dendritic cell vaccine

Dendritic cell (DC) is a professional antigen presenting cell (APC), which can efficiently present and activate MHC I and MHC II to CD8+ and CD4+ T cells. Stimulating memory T cells and memory B cells produce specific anti-tumor responses and play an important role in primary and secondary immune responses against tumors.

1.2.3. Vaccine combination therapy

1.2.3.1. Immunological checkpoint treatment and vaccine combination therapy

Immunological checkpoints are key to maintaining immune tolerance to chronic antigen exposure and preventing tissue damage. T cell activation is dependent on the interaction between co-stimulatory, co-inhibitory receptors and their ligand complexes. Usually, co-stimulatory receptors have CD40, CD28, OX40 and 4-1BB, while inhibitory receptors have CTLA-4, PD-1, B7 family receptors and their ligands CD80, CD86, PD-L1 and PD-L2. . Immunological checkpoint therapy is an antibody based on the inhibitory receptors CTLA-4, PD-1 and its ligands.

1.2.3.2. CAR-T Cell Therapy

The chimeric antigen receptor (CAR) is a type of genetically engineered transmembrane fusion receptor that binds to primitive cell surface antigens and transmits specific T cell activation signals. CAR-T cells (CAR-T) are a type of T-cells that are genetically engineered to encode tumor-specific antigen receptor genes, which allow T cells to express related antigen receptors and restore T cells. Immune surveillance can identify tumor surface antigens, so that a large number of tumor-associated antigens released by tumor cell rupture are presented, which can trigger the recognition and complete killing effect of the body’s immune system on tumors, which can be regarded as a special kind of cell vaccine. The key to developing CAR-T cell therapy is to select the appropriate targeting antigen and immune receptor.

2.Colon cancer vaccine

Colon cancer is one of the high-grade malignant tumors of the digestive system. The incidence rate is the third in the world for malignant tumors and has risen to the second place in economically developed areas. The emergence of coloncancervaccine will definitely bring new hope to the treatment of colon cancer.

Tumor vaccines use tumor cells or tumor antigens to induce the body to produce immune responses against tumor cells, inhibit their growth, and prevent recurrence and metastasis. Tumor antigens have been found on the surface of spontaneous tumors and human tumor cells in animals. Tumor antigens are generally classified, and two anti-tumor antigen classification methods including tumor-specific antigen (TSA) and tumor-associated antigen (TAA) are introduced. TSA is only present on the surface of tumor cells and is an antigen unique to a certain tumor cell. TAA is unique to non-tumor cells and is an antigen that can be expressed by normal cells. However, when cells are cancerous, their content is significantly increased, and such antigens only show quantitative changes without

Strict tumor specificity, embryonic antigen is a typical representative of it. Embryonic antigen refers to the normal component produced by embryonic cells during embryonic development. It is reduced in the late stage of embryonic development, gradually disappears after birth or remains extremely small, and such antigens regenerate when the cells become cancerous. At present, there are two kinds of embryo antigens that are the most intensive: 1) Alpha-fetoprotein (AFP): a glycoprotein synthesized by fetal liver cells, which inhibits maternal immune rejection. Adults are almost undetectable, and hepatocellular carcinoma is abundantly expressed when it is cancerous. 2) Carcinoembryonic antigen (CEA): It is an antigen that loosely binds to the cell membrane and is easily detached, such as carcinoembryonic antigen produced by intestinal cancer cells. AFP and CEA are weakly immune, as they have emerged during the embryonic period, and the body’s immune system has been immune to it and does not produce an immune response. However, AFP and CEA can be used as tumor markers to detect the early diagnosis of primary liver cancer and colon cancer by detecting the levels of AFP and CEA in the serum of patients.

At present, the main research tumor vaccines include the following:

2.1. Inactivate tumor cell vaccine

The tumor cell vaccine extracts tumor cells from the tumor tissues of the body, and inactivates the tumor cells that have lost the tumorigenicity but still maintains their immunogenicity, thereby inducing the body’s active immune response. In theory, such vaccines can provide tumor antigens, including TSA and TAA, to induce the body to produce an anti-tumor immune response.

2.2. Dendritic cell vaccine

Dendritic cells (DC) vaccine (referred to as DC vaccine) is the most active and fruitful biotherapeutic topic in research today. DC can be used as an important component of tumor immunotherapy. The mechanism of DC vaccine for malignant tumors is as follows: 1) Dendritic cells are special antigen-presenting cells, which help the immune system recognize tumor cells; 2) DCs carrying tumor antigens will antigen The information is presented to and activated by T cells, which induces the body to produce a large number of T lymphocytes with specific cytotoxic functions, which have specific killing effects on tumor cells. Dendritic cell therapy is a very cutting-edge new technology, and the application of DC vaccine has brought good news to the treatment of cancer patients. Numerous studies have shown that DC vaccines are safe, easy to handle, and immunosuppressive for a range of tumor types. The safety of the DC vaccine is also very good, and there have been no reports of serious adverse reactions. The successful development of dendritic cell vaccine treatment has brought new hopes to countless tumor patients and opened up a new way for the treatment of cancer.

2.3. Protein or polysaccharide vaccine

Such vaccines are obtained by mixing or linking tumor-associated proteins or polysaccharides and adjuvant molecules into the human body to induce humoral or cellular immunity, thereby achieving the purpose of killing tumor cells. The reason why tumors cannot be recognized by the immune system is mainly due to the weak immunogenicity of tumors. Therefore, the use of immunoadjuvants to enhance the immunogenicity of tumors is a hallmark of early tumor vaccines. The protein or polysaccharide vaccine is composed of an adjuvant such as Corynebacterium, alum, BCG, Freund’s complete adjuvant, etc. in the lysate of autologous or allogeneic tumor cells or tumor cells. Its mechanism of action may be related to the activation of antigen presenting cells (APC) by the inflammatory response at the injection site, the production of cytokines and the accumulation of B and T cells around the antigen.

2.4. Gene vaccine

Gene therapy is a hot research area in current medicine and biology. Gene vaccines, also known as nucleic acid vaccines or DNA vaccines, are often referred to as “naked” DNA vaccines. It contains no peptide, protein or viral vector, but consists of an antigen-encoding gene derived from the pathogen and plasmid DNA as its carrier. The birth of the genetic vaccine has revolutionized the treatment of colon cancer patients. : It is easy to operate and can be easily controlled by increasing or decreasing the amount of DNA injected. It does not require complex processes such as separation and purification of proteins. One or two weeks after DNA vaccine injection, an immune response is produced. After 14 days, the expression in the muscle is reached. The peak, then gradually decline, remains at low levels for months or even 1 year. In recent years, many researchers have actively developed tumor-related gene vaccines. The preliminary experiments have also proved that genetic vaccines have good curative effect and high immune performance, which makes people have a strong interest and expectation for the development of genetic vaccines.

The use of tumor vaccines can cause specific immune responses, thereby inhibiting tumor growth. Although tumor vaccines use the patient’s own tumor cells, tumor-specific antigens and other immune-regulatory cells to treat and prevent tumors, opening up a modern way to safely and effectively treat tumors, but at present, there are some difficulties in the development of tumor vaccines, such as further regulation. Enhance immune effector cells, etc. Once these problems are resolved, the tumor vaccine can be used on a large scale in the clinic. In addition, due to the complex composition of human tumors and the heterogeneous expression of tumor antigens, it may be necessary to immunize with a variety of tumor antigens in order to induce an effective immune response in patients.

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