One step closer to a cancer vaccine
For ten years, scientists from Arizona State University have been trying to develop a universal cancer vaccine. They found 200,000 neoantigens repeated in different types of tumors, which opens up new possibilities for creating a single vaccine against all types of cancer.
To detect these neoantigens, scientists studied mutations in more than 50 cancer cell lines and 85 tissue samples, as well as the blood of patients with 5 different types of late-stage cancer: cancer of the lungs, breast, brain, stomach and pancreas.
A new common source of tumor mutations has been found, which can be used to create 3 types of vaccines:
- universal cancer vaccine;
- specific cancer vaccines (e.g. pancreatic or breast);
- personalized cancer vaccines based on mutations unique to a particular person.
In order to detect neoantigens in cancer patients' tumors, scientists developed a new type of chips that presented all 200,000 possible neoantigens, which allowed them to screen antibodies in patients' blood. This is much easier than the usual practice of obtaining and sequencing DNA from a tumor to create personalized cancer vaccines. This process requires a lot of effort and money, in addition, only 40% of tumors have specific antigens on the basis of which a vaccine can be created.
The mutations that this research group focuses on – peptides with a reading frame shift – are much more immunogenic than the point mutations used in personalized cancer vaccines. This approach makes it possible to create cheap vaccines that can be used both for therapeutic and preventive purposes.
Studies in mice have shown that these neoantigens perform a protective function, both in the breast cancer model and in the melanoma model. Recently, these data were used to launch a large preclinical study of universal preventive cancer vaccines in dogs.
Neoantigens are small fragments of proteins inside a cancer cell that the host's immune system has never seen before. Such aberrant peptides in the vaccine can stimulate the immune system.
As it turned out, neoantigens appear as a result of errors that occur during RNA splicing. These errors occur due to a violation of the reading of the genetic code.
For the most part, incorrectly read proteins can be destroyed inside the cell without ever encountering the immune system. As the cancer progresses, as a result of an increase in the number of errors, protein debris accumulates faster, suppressing the vital activity of the cell, and aberrant proteins are recognized by the immune system.
In order to quickly identify frameshift mutations (gene reading frame shift mutations) and splicing disorders, scientists have developed a data array to detect all possible peptides synthesized after frameshift, which any tumor cell can potentially produce. The array contains 400,000 frameshift peptides, and was tested on the blood of cancer patients (and healthy patients as a control) to find those peptides that had the most reactive antibodies.
According to the results of the tests, it turned out that:
1) the vast majority of frameshift peptides (69%-80%) are unique for each individual.
2) 16%-19% of peptides coincide within 2 different types of cancer.
3) 1.5%-6.9% were divided between three or more types of cancer (stomach cancer has the highest percentage of similarity with other types of cancer – 6.9%).
It is striking that one of the most difficult types of cancer to treat, glioblastoma, has the greatest potential for creating personalized vaccines. Of the 17 studied samples of patients with glioblastoma, each patient had 5,800 peptides, and 4,500 of them were unique.
The scientists then compared 20,000 peptides that they identified in the late and early stages of pancreatic cancer. It turned out that there is little in common between peptides at different stages, which in turn suggests that vaccines for different stages of the disease should also be different. All the changes in the structure, identification and screening experiments allowed them to select the best candidates for the vaccine, which were tested on 6-week-old mice by injection into the auricle. After 4 weeks, they began to be injected with cancer-causing drugs, after which they began to make booster injections every 2 days.
It turned out that vaccines can significantly delay or even prevent the growth and development of a tumor. It was also found that combining several frameshift peptides led to a significant delay in tumor growth and made the vaccine more effective.
Based on the analysis of various cancer samples and problems with vaccines in mice, scientists have created a list of the "100 best" peptides for each of the 5 types of human cancer. At the moment, scientists are doing their best to move on to the first clinical trials in humans.
Article by Shen et al. RNA Transcription and Splicing Errors as a Source of Cancer Frameshift Neoantigens for Vaccines is published in the journal Nature Scientific Reports.
Elena Panasyuk, portal "Eternal youth" http://vechnayamolodost.ru based on Arizona State University: Discovery may expand cancer vaccine capabilities.