Individualized immunotherapy for malignant tumors using peptide-based vaccines
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Immunotherapy is considered one of the most rapidly developing areas of oncology. For most cancers, doctors already use immune checkpoint inhibitors, and they have become part of standard cancer treatment. Monoclonal antibodies, antibody-drug conjugates, and CAR T-cell therapy are successfully used for some oncological diseases.
Scientists associate future successes of immunotherapy with such a direction as cancer vaccines. In recent years, the attention of researchers has been focused on neopeptide vaccines, which are created on the basis of unique tumor cell antigens. Such vaccines are created individually for each patient.
Content
- How do peptide-based cancer vaccines work?
- What are neopeptide vaccines?
- Stage 3: dendritic cell-based vaccines
- Enhancing the effectiveness of peptide-based vaccines
- How are neopeptide vaccines produced and used?
- Where to undergo treatment using peptide-based vaccines?
How do peptide-based cancer vaccines work?
During the development of cancer vaccines, many varieties of them have appeared, for example, peptide-based vaccines, genetic vaccines, and dendritic cell-based vaccines. They have a different principle of action, but the goal is the same: to "show" the immune system a target for attack and enhance the antitumor immune response.
Peptide-based vaccines, as their name implies, use peptides to stimulate the immune system. They are small proteins made up of several amino acids. They are antigens that can trigger an immune response. Scientists find such antigens in tumors and create a vaccine based on them. These peptides are injected into the body and trigger an immune response. Antigen-presenting cells can therefore see antigens, learn them, and then transmit the information to T cells, which attack the tumor.
The advantage of this type of treatment is that it is systemic. The antitumor immune response is launched not in a single place but throughout the body. This means that all cancer cells will be attacked, including those in places where metastases have spread and where accumulations of cancer cells have not yet been detected by radiation methods.
Although this sounds attractive in theory, scientists have encountered many problems in the development and use of peptide-based vaccines in practice. Therefore, we still do not have any such vaccine approved for clinical use. The development, however, continues, technologies improve, and emerging problems are gradually solved, so it can be expected that in the near future, peptide-based vaccines will become part of the standard cancer treatment, as happened with other methods of immunotherapy.
What are neopeptide vaccines?
Early vaccination strategies that targeted tumor-associated antigens were unsuccessful. Why? This is likely due to the fact that immune T cells are prone to tolerance to these antigens. They do not fully perceive tumor cells as foreign because tumor antigens, as a rule, are present in normal tissues, although in smaller quantities.
Another problem associated with these antigens is possible autoimmune reactions. If T cells attack the tumor and there are similar "targets" in normal tissues, inflammation of the organs containing tumor-associated antigens simultaneously develops.
Therefore, in recent years, scientists have focused on the search for unique antigens that are present in cancer cells but are completely absent in normal tissues. They are more immunogenic, and vaccines based on such peptides will be safer.
Research shows that mutations that occur in tumor cells generate new epitopes of their own antigens. They are called neoepitopes or neoantigens. In developed countries, they are working on the development of vaccines specifically against neoantigens. This strategy seems more promising because these vaccines will be more specific. They will not attack normal tissues, as there are simply no new antigens in them. In addition, when using such vaccines, scientists do not face the problem of central tolerance when T cells "do not want" to attack the tumor. Finally, another advantage of neopeptide vaccines is immunological memory, due to which such a vaccine will protect against cancer recurrence for many years.
What are neopeptide vaccines made of?
All neoantigenic vaccines are personalized. These include several types of drugs that are made on the basis of dendritic cells, DNA, mRNA, and synthetic peptides.
Vaccines based on synthetic peptides are considered the most promising direction. This is evidenced, at least, by the fact that more than half of all studies evaluating the effectiveness of vaccines that are currently being conducted in the world are devoted to them.
These vaccines are made of:
- A peptide (a low molecular weight protein) or mixture of peptides
- An adjuvant that stabilizes the peptide and enhances the immune response
Neopeptides come from proteins found in cancer cells. The manufacture of such vaccines requires taking short immunogenic fragments containing up to 10 amino acids. Such molecules easily penetrate the tumor. It is also possible to use longer fragments, up to 30 amino acids, but in this case, an additional processing step is required for cleavage into immunogenic peptides.
In 2019, the NeoPeptide database was created. It contains important information about neopeptides that allows scientists to identify neoantigens in different types of cancer and find suitable candidates among tumors for the creation of neopeptide vaccines against them.
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Enhancing the effectiveness of peptide-based vaccines
Despite the prospects of this direction, the success of clinical applications is still limited. The main problem lies in the immunosuppressive (suppressing immunity) tumor environment. The specialists try to solve this problem with the help of adjuvants and the combined use of vaccines with cytostatics (drugs for chemotherapy) and immune checkpoint inhibitors, which remove the "mask" from the tumor and enhance the T cell response.
Adjuvants are used to increase inflammation and unblock dendritic cell function. Good results are shown through the use of the following adjuvants:
- Poly-ICLC mimics a viral infection, enhancing the synthesis of interferon and cytokines
- GM-CSF stimulates the maturation of cells in the bone marrow and activates dendritic cells, neutrophils, and macrophages
- CAF®09b is a new adjuvant that activates dendritic cells and enhances the T cell response
- ISA 51 VG is a montanide (a mixture of mineral oil and a surfactant) that attracts antigen-presenting cells to the vaccine injection site
How are neopeptide vaccines produced and used?
All neopeptide vaccines are made individually. Tumor mutations are rarely common, even for two identical tumors. In addition, each patient's immune system is unique.
It takes 12 to 24 weeks to produce a vaccine. This prevents the use of vaccines and checkpoint inhibitors at the same time. Doctors therefore start immune checkpoint inhibitor therapy, and a few months later they add the vaccine.
Vaccine production begins with the identification of tumor-specific gene variants using NGS sequencing (next generation sequencing). To do this, tumor tissue is compared with normal tissue. The required peptides are then synthesized and purified to 90-98% by reversed-phase liquid chromatography. Purified peptide fractions are lyophilized at a temperature of minus 80 degrees, which results in a powder with a final degree of purity of more than 95%.
Peptides are dissolved in a solvent. The dose per administration is 0.1-0.3 mg of peptides. The vaccine is injected subcutaneously, after which the peptides are taken up by antigen-presenting cells at the injection site. In turn, these cells "train" T cells by providing them with information about targets to attack. The result is a T cell immune response causing tumor destruction.
No vaccine is currently approved for clinical use, but a significant number of peptide-based vaccines are under clinical trials, including such drugs as NeoPepVac, NeoVax, iNeoVac-P01, PNeoVCA, PANDA-VAC, FRAME-001, and GEN-009. In research, peptide-based vaccines are used for melanomas, glioblastomas, follicular lymphomas, lymphocytic leukemias, kidney cancer, ovarian cancer, esophageal cancer, pancreatic cancer, and lung cancer.
Where to undergo treatment using peptide-based vaccines?
Since peptide-based vaccines are not yet included in the standard cancer treatment regimen, this technique can be used when participating in clinical trials that are conducted in developed countries.
If you want to take advantage of the latest advances in immunotherapy, you are welcome to get advice from the Booking Health specialists. We will assist you in selecting the most suitable hospital, come there for treatment, and become a participant in a clinical trial for the treatment of cancer using peptide-based vaccines.
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Authors:
The article was edited by medical experts, board certified doctors Dr. Nadezhda Ivanisova and Dr. Vadim Zhiliuk. For the treatment of the conditions referred to in the article, you must consult a doctor; the information in the article is not intended for self-medication!
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