Viral primer and bacterial booster
Virus and bacterium-based cancer vaccine
Anastasia Gorshkova, PCR.news
One of the promising strategies for cancer treatment and prevention of its recurrence is immunotherapy with the use of vaccines. With their help, the human immune system trains to recognize an antigen that is present in cancer cells and absent in normal ones, thereby acquiring the ability to destroy cancer cells and prevent its recurrence. As a rule, modified viruses or modified bacteria are used in such vaccines. In a new study, scientists from Thomas Jefferson University (Philadelphia, USA) have shown on an animal model that the combined use of vector vaccines based on the adenovirus Ad5.F35 and the bacterium Listeria monocytogenes (Lm) helps fight cancer much more effectively than their use separately.
"The platforms for creating vaccines are not unique," says the head of the work, Dr. Adam Snook, professor at the Sydney Kimmel Cancer Center at Jefferson University. "But no one combined them into a combined vaccine, and that's how we were able to see an increase in the immune response."
Earlier, the same team of scientists used a modified strain of adenovirus Ad5.F35 as the basis for a vaccine that trains the immune system of patients to identify and attack cells expressing a certain protein. It is known that guanylate cyclase C, known as GUCY2C, is present in almost all colorectal cancer cells and is practically absent in other tissues. Scientists have created and tested the vaccine Ad5.F35-GUCY2C, the action of which is based on the expression of GUCY2C and the activation of T cells that recognize this antigen. This drug is currently in phase 2 clinical trials.
The problem is that the effect of an adenovirus-based vaccine does not last long, so an additional dose is needed to consolidate the effect. However, when the same Ad5.F35 vector is reintroduced, the expected response does not occur due to the immunological memory for it. In order for the immune system to continue fighting cancer, the body needs a different type of booster vaccine. It is known that previous listeria infections do not cause the formation of neutralizing antibodies.
The adenovirus vaccine was administered intramuscularly to mice, and the bacterial vaccine was administered intravenously. The two platforms together really worked much better than either of them separately. Vaccination did not cause intoxication and inflammation in animals, which indicates good tolerability and absence of undesirable effects. The scientists found that, compared with homologous vaccination, the use of two different components — Ad5.F35 and Lm — increased the number of GUCY2C-specific CD8+ T cells. The pool of these cells ceases to be predominantly monofunctional, that is, consisting of cells that produce only one cytokine, it is saturated with multifunctional T cells. They have also become more avidious (able to be activated from lower concentrations of antigen); as the authors note, further research is needed to understand the relationship between increased avidity and polyfunctionality. Interestingly, the bacterial component of the vaccine alone turned out to be completely ineffective.
The vaccination scheme was tested on a mouse model of recurrent metastases of colorectal cancer. Vaccination with adenovirus and bacteria carrying the GUCY2C gene (the red line in the figure below is VM) significantly reduced the metastatic tumor mass and increased the survival rate of animals compared to the control and any other vaccination regimens. The order of doses mattered: for maximum effect, the adenovirus should be prime and the bacterium boost.
Further studies will determine whether such a strategy is capable of preventing cancer recurrence in patients. Combined vaccines can also help in the development of remedies for HIV and malaria: the authors believe that such platforms can work very well against these diseases.
Article by Flickinger et al. Chimeric adenoviral (Ad5.F35) and listeria vector prime-boost immunization is safe and effective for cancer immunotherapy published in the journal npj Vaccines.
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