As a means of preventing infectious diseases, vaccines play an irreplaceable role in the process of human beings to overcome diseases. For example, vaccination against vaccinia has eliminated smallpox on a global scale. With the in-depth study of immunological mechanisms and the rapid development of biotechnology, prevention and treatment of cancer has become a new development direction in the field of vaccinology research.
1. Preventive Cancer Vaccine
Studies have found that chronic persistent infections of some viruses are closely related to the occurrence of cancer, such as the relationship between hepatitis B virus (HBV) and liver cancer, and the relationship between high-risk type of human papillomavirus (HPV) and cervical cancer. The development of such viral vaccines can be used for the prevention of cancer. In June 2006, the US FDA approved Merck’s four-valent HPV vaccine, which includes high-risk HPV16, 18 and low-risk HPV6, 11 (low-risk type is mainly used to prevent condyloma acuminata). The prophylactic HPV vaccine uses genetic engineering techniques to utilize the master of the HPV virus.
The capsid protein (LI) can be self-assembled into the characteristics of virus-like particles (VLP), expressed using yeast cells, and isolated and purified in combination with aluminum adjuvant. The phase III clinical data showed that the vaccine had good immunogenicity, and the antibody remained at a high level after 5 years of immunization, and induced strong immune memory.
2. Therapeutic Cancer Vaccine
Studies suggest that the occurrence and development of tumors are related to immune tolerance and immune escape. After artificially inoculation of vaccines made of tumor antigens, it is possible to break the tolerance of the autoimmune system to tumor antigens and activate tumor-specific T cells or Induces tumor-specific antibodies, activates immune recognition, and achieves the purpose of killing tumors.
Various methods are currently being tried to induce immune responses to therapeutic cancer vaccines, such as selecting different tumor target antigens, using different adjuvants, and isolating antigen presenting cells for in vitro treatment.
Depending on the use of target antigens and vaccine preparation methods, therapeutic cancer vaccines can be easily divided into the following categories:
2.1 Autologous cancer vaccine
This type of vaccine uses the patient’s own tumor cells, which are not irradiated by extracorporeal radiation treatment, and then inoculated to the tumor patients themselves. Since the cells of the autologous cancer vaccine are derived from the tumor of the patient’s own growth, containing the holographic antigen, the potential ability to induce an immune response is inoculated after the patient is inoculated. However, since it is derived from autologous, it is generally required to be conjugated with an immunological adjuvant or hapten to enhance immunogenicity and then inoculated. This type of vaccine is specific and can be used to prepare corresponding vaccines for specific individuals, but it also has limitations such as time-consuming and labor-intensive.
Onco-VAX R (cancer vaccine development), an autologous cancer vaccine developed by Intracel in the United States, has achieved some success in Phase III clinical trials. The vaccine was a radiation-treated whole-cell vaccine with intradermal injection of 107 cells at 0, 1, 3 and 6 months, respectively. The autologous vaccine for the treatment of melanoma developed by Berd and colleagues also uses a radiation-treated whole-cell vaccine with BCG as an adjuvant. It is treated with a low dose of cyclophosphamide before use. The vaccine is conjugated to a hapten. Significantly enhanced. Another type of autologous cancer vaccine is the use of lysed autologous tumor cells. This method is used in the autologous vaccine developed by LipoNova in Germany for the treatment of renal cell carcinoma. The autologous cells used in the early trials were from nephrectomized tissues, and the cells were treated with IFNc and tocopherol. The patients were vaccinated 4 weeks after surgery and inoculated twice, 4 weeks apart.
2.2 Allogeneic cancer vaccine
Such vaccines are prepared from tumor cell lines from different individual patients and are induced to produce an immune response by similarity between the tumor antigen in the vaccine and the tumor tissue of the vaccinator. In order to cover as many antigens as possible, cells containing a plurality of tumor cell lines are generally included. As with autologous cell tumor vaccines, radiation or other methods are used to inactivate cells before vaccination.
Mitchell et al. first reported the results of the use of allogeneic tumor cell vaccines in 22 patients with metastatic melanoma in 1988. Onyvax-P, an allogeneic tumor cell vaccine developed by Onyvax for the treatment of androgen-independent prostate cancer, consists of three cell lines (OnyCap23, LnCap and P4E6), which represent the characteristic antigens of the disease at different locations. A randomized, multicenter, placebo-controlled Phase IIb clinical trial is currently underway for further analysis of these results. CancerVax has developed the allogeneic melanoma vaccine Canvaxin, which consists of three different melanoma cell lines (M14, M24 and M101) using BCG as an adjuvant. In a phase II clinical study, patients with grade III melanoma were vaccinated with Canvaxin, and the survival rate was significantly improved in the same time period compared with the uninoculated control group. However, in a multicenter, randomized phase III clinical study, the results of the vaccine group ended earlier than the placebo group. Antigen-specific immunity leading to antigen-specific escape may be one of the reasons.
2.3 Peptide vaccine
Such antigens are composed of one or more antigenic peptides containing different epitopes of tumor cells, exhibiting tumor antigen specificity, and can induce tumor-specific T cells after inoculation. The HER -2 vaccine for the treatment of breast cancer does not involve cell culture in the preparation of such vaccines. It is simpler than the first two therapeutic vaccines and has the most extensive clinical trials. However, since the antigens generally expressed by tumor cells are very complicated, most of the epitopes are not known, and only a limited epitope is included in the polypeptide vaccine, and the gene mutation is likely to cause antigen loss and mutation after inoculation. The gpl00 polypeptide vaccine was used to treat gpl00 melanoma. After vaccination, the CTL specific for gpl00 increased, but the tumor did not disappear. The newly grown tumor did not express gpl00 antigen, and lymphocytes isolated from these sites did not react with gpl00. These lymphocytes reacted with MAGE-12 antigen, but the antigen component was not included in the vaccine. In addition, after the polypeptide vaccination, it needs to be presented to the helper cells in combination with the MHC molecule, so that the expression of the tumor-associated polypeptide can be affected when the expression of the MHC molecule on the surface of the tumor cell is decreased or the polypeptide is transported abnormally.
2.4 DNA vaccine
DNA vaccines generally refer to a class of vaccines that use recombinant plasmids to introduce tumor antigens. The recombinant DNA expresses the foreign tumor antigen after entering the cell through different routes (intramuscular injection, subcutaneous injection, etc.). Compared to peptide vaccines, their immunogenicity can last longer. Moreover, endogenously expressed tumor antigens can avoid the requirement of HLA matching.
The current use of new inoculation methods such as gene gun, electroporation and simultaneous use with new adjuvants will increase the immunogenicity of DNA vaccines and induce a stronger immune response.
2.5 Viral Vector Vaccine
Recombinant viral vectors have higher transduction efficiency than DNA vaccines and can accommodate large foreign genes. For example, poxvirus vectors can accommodate foreign genes up to 30 kb, so multiple expressions can be expressed simultaneously in the same viral vector. Source antigen. Viral vectors can also induce strong innate immune responses that facilitate the production of antigen-specific T cells. Poxvirus vectors and recombinant adenoviral vectors are currently studied in a variety of viral vector vaccines. The genes of these two vectors are stable, and many clinical studies have shown certain immunogenicity and safety.
Transgene has developed the MV-A-MUC1-IL2 vaccine to evaluate its role in lung cancer and prostate cancer. The vaccine showed good immunogenicity after inoculation, especially in patients with 1Hb and IV lung cancer, and achieved better results when combined with chemotherapy. Most of the tumors in patients with grade IV lung cancer express MUC1, and this tumor marker is associated with poor prognosis. The survival rate of patients after vaccination is related to the cellular immune response of MUC1. A phase II clinical trial of the MVA-MUC1-IL2 vaccine was conducted in 65 lung cancer patients to evaluate the effects of simultaneous use of vaccines, chemotherapy, and chemotherapy alone. The results showed that the vaccine was well tolerated and the patient developed a MUC1-specific cellular immune response after vaccination.
Some studies have shown that the immunogenicity of recombinant adenoviral vector vaccines is difficult to achieve the desired results. In a phase I study involving 54 melanoma patients, all patients were vaccinated with a recombinant adenovirus vaccine encoding MART-1 or gplO0 melanoma antigen (vaccinated only or simultaneously with IL-2) N51. Only one of the 16 patients vaccinated with the adenovirus-MART1 vaccine developed an immune response, but the response may also be induced by IL-2.
When multiple immunizations using the same viral vector vaccine will stimulate the body to produce antibodies against the antiviral vector, in order to solve this problem, the pre-El application is more to use DNA vaccine in the initial immunization, and then use the viral vector vaccine to strengthen. Studies have shown that the above immune sequences cannot be induced to produce high levels of antigen-specific CD8+ T cells when inverted. The reason may be that cytokines produced by local viral infection during booster immunization facilitate the expansion of effector T cells.
2.6 Dendritic cell vaccine
Dendritic cells (DC) are the most effective antigen presenting cells. After entering the human body, the antigen is engulfed, processed by dendritic cells, and then presented to lymphocytes. DC vaccine refers to the collection of autologous or allogeneic dendritic cells, which are incubated with tumor antigens in vitro and matured and inoculated into humans. The use of such vaccines can theoretically avoid the antigen processing and presentation process when inoculated with whole-cell vaccines, or the number of antigen-presenting cells inoculated at the site of inoculation of polypeptide vaccines and DNA vaccines. In addition, you can choose to use the desired dendritic cell line, especially the specific maturation signal and the inoculation site, so that you can better control the immune response.
A widely used method is to separate dendritic cells from monocytes or CD14-positive cells, and immature dendritic cells are produced after culturing in GM-CSF and IL-4, and then incubated with tumor antigens. After inoculation, it is inoculated subcutaneously or intradermally. Dendritic cells can also be directly inoculated into the interior of the tumor. This in situ vaccination method has been shown to have a role in animal testing for unresectable cancer.
To be continued in part two…
Reference
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