How the Universal Cancer vaccine works
Antiviral protection system can be used for effective immunotherapy of cancer
Vyacheslav Kalinin, "Elements"
Fig. 1. Mechanism of action of RNA-lipoplex anti-cancer vaccine.
a – RNAs in the composition of the lipoplex specifically penetrate into the precursors of dendritic cells, induce their maturation and migration to T cells. The penetration of nanoparticles into other dendritic cells induces the synthesis of interferon, which promotes the activation of T cells.
b – translation of RNA in maturing dendritic cells gives an antigen that is presented to T cells. The capture of nanoparticles by macrophages gives a second wave of interferon, as a result of which T cells are fully mobilized against a specific antigen.
c – mobilized T cells attack tumor cells. A drawing from the synopsis to the discussed article in Nature.
German scientists have managed to create a fundamentally new anti-cancer vaccine. They packed the matrix RNA of genes specific to cancer cells into special nanoparticles and forced them to target the dendritic cells of lymphoid tissues. As a result, dendritic cells "instructed" T-lymphocytes and directed them to attack the cancer antigen, that is, cancer cells. Tests on mice and even on patients with melanoma have shown high therapeutic and preventive efficacy of the new vaccine.
Methods of non-surgical cancer treatment are constantly being improved. But even such mass methods as radiotherapy and chemotherapy are not always effective and selective enough, have side effects and can cause complications. For example, cytostatic chemotherapy is very difficult for patients to tolerate.
Recently, methods of immunotherapy for cancer and other intractable diseases have been increasingly being developed. So, recently we discussed the work on the creation of bivalent antibodies in relation to the human immunodeficiency virus (Bispecific antibodies can destroy hidden reservoirs of HIV infection, "Elements", 02/16/2016). This method can also be adapted to the targeted delivery of T-killers to cancer cells. But an undesirable immune response may develop to foreign antibodies used in such systems. Therefore, research is actively being conducted to mobilize and strengthen the body's own immune response to a cancerous tumor associated with T-lymphocytes.
The cellular immunity system is remarkable for its flexibility and efficiency. One of the important components of this system is the so–called antigen-presenting dendritic cells. They are localized in lymphoid organs (spleen, lymph nodes, bone marrow) and are able to absorb antigens foreign to the body, split them into individual peptides and expose these peptides on their surface for "viewing" by other cells, primarily T cells. Thus, dendritic cells "train" T cells and direct them to attack the desired antigen.
Dendritic cells seem to be an ideal tool for the effective initiation and enhancement of the T-cell immune response to a foreign antigen. Usually in the body, this mechanism is aimed at neutralizing viral infections. But a large team of scientists from several scientific institutions in Germany managed to adapt it for immunotherapy of cancerous tumors. It is important to emphasize that this is a very non–trivial result, because the immune system usually does not perceive cancer cells as enemies (recognition of "friend - foe" does not work well, because cancer cells are, in general, "their own"), and also because tumor formation is often not accompanied by the release of any- or specific antigens. Moreover, cancer cells have been evolving inside the body for a long time in constant contact with the immune system, so they are affected by a kind of selection for the ability to resist the immune response.
The scientists decided not to load dendritic cells with a ready-made antigen specific to cancer cells and absent in mature normal cells, but to give them the opportunity to synthesize it themselves on the basis of the corresponding mRNAs. The difficulty, however, is that in the bloodstream free RNA is rapidly decomposed by actively working nucleases. Therefore, special nanoparticles – lipoplexes (a kind of DNA vaccination method) were used to deliver "antigenic" RNAs to the precursors of dendritic cells. These are layered structures in which lipid membranes protect mRNA (Fig. 2).
Fig. 2. Schematic representation of the lipoplex. Charged hydrophilic heads of lipids are indicated in red, lipid tails are indicated in gray, and DNA or RNA molecules are indicated in blue. The lipid component in the bloodstream protects the nucleic acid from decomposition by nucleases. Drawing from the website ru.wikipedia.org
The first problem to be solved was the targeted delivery of these lipoplexes to lymphoid tissues, where dendritic cells are localized and T cells are activated. It turned out that nothing superfluous needed to be added for this: scientists managed to find the ratios of mRNA and lipids, in which, after intravenous administration of lipoplexes, mRNA expression was observed almost exclusively in the lymphoid tissues of mice – spleen, bone marrow and lymph nodes (Fig. 3).
Fig. 3. b – dependence of the mRNA expression site on the lipid/RNA ratio (the numbers above the mouse images). The three right groups of images and pie charts show that with a certain ratio of RNA and lipids, mRNA is expressed almost exclusively in lymphoid tissues. Spleen – spleen, lungs – lungs, liver – liver.
g – expression of luciferase mRNA injected into the blood as part of lipoplexes (lower row) occurs in isolation in lymph nodes (LN) and bone marrow (Bones).
Free RNA (upper row) is destroyed in the bloodstream, without reaching the lymphoid organs. A drawing from the discussed article in Nature.
To study the biological effects – the body's response to mRNA expression in dendritic cells – model experiments were first conducted. The lipoplexes were loaded with RNA encoding hemagglutinin of the influenza virus. As a result of intravenous administration of such particles in the spleen, maturation of dendritic cells and activation of various types of T cells were observed. This was accompanied by activation of interferon alpha expression characteristic of the antiviral immune response. If the lipoplexes were loaded with mRNAs encoding an ovalbumin fragment that was labeled with melanoma cells, or encoding the glycoprotein gp70 of the mouse leukemia virus, then the production of T cells against these antigens and cells was observed. As a result of three-time administration of such lipoplexes, the immune response was "remembered" and provided protection after transplantation of the corresponding tumor cells. At the same time, non-immunized mice died within 30 days after transplantation.
To determine the effectiveness of such treatment, a number of cancer models were tested on mice. Thus, triple administration of lipoplexes resulted in complete cure of melanoma metastases in the lungs within 20 days after the last immunization (Fig. 4). Similar results were obtained in other models, as well as in monkeys. No unacceptable side effects were observed in mice or monkeys when lipoplexes were administered.
Fig. 4. Suppression of the growth of aggressive tumors in mice as a result of the administration of the mRNA-lipoplex vaccine. Mice were injected with cultured colorectal cancer cells of mice ST26, into which the luciferase gene was introduced. These cells express the gp70 antigen, which is not present in normal cells. The upper row in the left group of images is control, the lower row is mice after regular immunization with the appropriate vaccine. At the top in the right group of images are the lungs of control and immunized mice, at the bottom is a bioluminescent image of these lungs (see Bioluminescent imaging of cancer cells in vivo). A drawing from the discussed article in Nature.
The results of detailed experiments conducted on model animals allowed the authors to obtain permission and test the new method on patients with advanced melanoma. Despite the fact that the sample is small (the tests were conducted on only three patients), the results obtained are impressive and look promising. Lipoplexes were loaded with mRNA of four different antigens peculiar to melanoma cells and injected into patients: first a small dose, and then four increased doses weekly. The injections were tolerated by the patients quite well, causing only symptoms of a cold. In all patients, there was an increase in interferon alpha synthesis and a sharp increase in T-cell production against the injected antigens. Regression of metastases in lymph nodes was observed in one patient. In the second patient, who had metastases removed before immunization, no new metastases were observed for seven months (up to the time of publication of the article). In the third patient, who had eight lung metastases before immunization, their further growth did not occur.
Thus, the authors managed to create a fundamentally new vaccine based on mRNA, which has a high therapeutic potential. For the first time in the history of the creation of such vaccines, tests were conducted not only on model animals, but also on patients who showed high anti-cancer efficacy (although, we emphasize once again, there are only three patients so far). Such a vaccine can be prepared quickly, it is relatively inexpensive, and mRNA can encode almost any tumor antigen. In general, the described approach to immunotherapy using mRNA nanoparticles opens up new prospects in the treatment of cancer.
Of course, the proposed immunotherapy system still needs to be further investigated. It is necessary to find out its applicability to other types of cancer, as well as to test a number of mRNA antigens that are expressed in tumors, but not in normal mature cells. It is also necessary to investigate the ability of other cells of the immune system (neutrophils, monocytes) to absorb nanoparticles and activate under their influence. There is still a lot of work to be done, but I want to believe that it will give good results.
Sources:
- Lena M. Kranz et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy // Nature. 2016. V. 534. P. 396–401.
- Jolanda De Vries, Carl Figdor. Immunotherapy: Cancer vaccine triggers antiviral-type defences // Nature. 2016. V. 534. P. 329–331.
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22.08.2016