19 November 2015

How to help the Immune system fight cancer

Immunostimulating vaccines


Therefore, for many years scientists have been trying to develop effective anti-cancer immunotherapy. There has been notable progress in this area – in particular, by improving drug delivery methods. It seems that targeted transport of active substances is the right way to heal the body.

For more than a hundred years, immunotherapy has been viewed as a potential weapon against cancer. In 1891, when there was no chemotherapy or radiotherapy, William B. Coley successfully treated people for cancer using substances secreted by bacteria [1]. It has now been shown that they had an immunostimulating effect [2]. However, in clinical trials, cancer treatment strategies based on attempts to activate the immune response have suffered a number of crushing defeats. But scientists continue to believe in success, making vaccines more and more complicated.

Anti-cancer immunity consists of several stages. Its key steps are: recognition of the antigen, presentation of the antigen by antigen-presenting cells, activation of effector cells, moving them to tumors, recognition and destruction of cancer cells [1]. Theoretically, each of these stages could underlie the development of a drug. It is also important to think not only about the fundamentals of acquired immunity, but also about how to mechanically deliver the medicine to the right place in the body [3]. Nanoparticles made of synthetic materials appear to be the most promising "transport" for the drug [4]. They can contain a set of different biomolecules that are designed to help each other stimulate the immune system, and then they will move all together. By varying the size of the synthetic carrier, it is possible to achieve drug delivery to the lymph nodes. It is possible to make the particle surface itself functional if adjuvants or antigens are attached to it. Adaptive immune response opens up many opportunities for the treatment of diseases, and now scientists around the world are trying to take advantage of them.

Fundamentals of the anti-cancer adaptive immune responseEvery day our body is attacked by various pathogens, such as viruses, bacteria, fungi, parasites.

Protection against them is provided by immunity, which is divided into two branches: innate and adaptive [5]. Innate immunity reacts quickly to the invasion of the most typical pathogens and destroys them, and adaptive develops for a longer time, but has almost unlimited plasticity.

The starting signal for triggering the mechanisms of adaptive immune response is the appearance of an antigen in the human body. Alien organisms have biomolecules in their composition that are not found in the host organism. They are the antigens. The immune system knows "its" proteins, and takes all the others as a danger signal. So, the first task is to find the antigen. At this stage, antigen-presenting cells deal with it, which are most often dendritic cells (DC) [6]. Having obtained the antigen, dendritic cells can activate T cells*, making them cytotoxic (capable of killing the pathogen). An important step in activation is the release of cytokines, substances that polarize T cells. Activation of T-cells occurs in lymphoid tissues, from where they come out fully armed and begin to search for a stranger by a known antigen, as in a sketch [1]. Having discovered the pathogen, they secrete special substances that destroy the target cell, and then move on in search of a new one [7].

* – Dendritic cells present fragments of foreign proteins on their surface as part of the main histocompatibility complex of the first or second classes and activate CD8+ or CD4+ T cells, respectively. Note that CD4+ often play an auxiliary role in the immune response. After activation, they differentiate into different types of helper cells, depending on the polarizing cytokines [8].

The immune system can serve as a weapon against cancerTheoretically, the immune system can stop oncogenesis by recognizing and destroying tumor cells [9].

Cancer cells also have antigens, because they, being derivatives of one organism, still differ in many ways from its ordinary cells. In general, cancer antigens are divided into two groups: either the whole tumor cell serves as an antigen, or some of its molecular derivatives. Mutant proteins, which normally have a different structure, can act as an antigen. Or such proteins that are produced in large quantities in the tumor, but are not normal. Distinctive signals can also be polysaccharides of the cell surface, as well as special DNA and mRNA. Some viruses (Epstein-Barr virus, human papillomavirus [10, 11] and hepatitis B and C viruses) can stimulate the development of tumors, so the products of their genes can also be a target for immunotherapy [12]. 


Based on various antigens, scientists are striving to develop anti-cancer vaccines that can activate T cells. However, cancer cells avoid the immune response in various ways [13, 14]*.

* – It's hard to believe with what ingenuity cancer cells circumvent the immune system. In particular, they "pretend" to be sick in the face of "guards"-macrophages, and they trustfully rush to help them [15]. Moreover, the tumor cells managed to find the "stopcock" of lymphocytes – special receptors that inhibit the development of immune reactions - and actively use it, hiding from our defense system. And oncoimmunology is only just gaining sufficient skills to counter "deceive deceivers" [16]. – Ed.

When proteins were discovered that theoretically could serve as antigens and activate the immune response against tumors, it turned out that it was not very convenient to use whole molecules. For vaccines, it is better to take fragments of proteins – peptides. They can bind directly to antigen-presenting cells without requiring pretreatment, and are fairly stable during storage. Due to these advantages, peptide-based vaccines are undergoing preclinical and clinical trials [17]. At the moment, the main problem of such vaccines is their weak immunogenicity and short duration of action. In part, the first difficulty is explained by the fact that cancer cell proteins are still produced by the host organism, and T cells react poorly to them. Many problems of immunostimulating vaccines are now being tried to solve by improving the methods of their delivery to the body.

Drug delivery is a key stage of immunotherapyNanoparticles made of synthetic materials are one of the options for drug transport.

There are substances that, once in the human body, begin to gradually decompose. Biologically active substances, such as antigens, can be placed inside a particle made of such a material. Then after the degradation of the protective layer (but not before!) the medicine will get into the blood. A particle can have several layers. Then the layers of the material will be destroyed gradually, and the active molecules will enter the body in stages for a long time. In this way, long-term therapy is achieved after a one-time vaccination. Together with the antigen, adjuvants are usually packed into a synthetic carrier – substances that enhance the immune response (usually these are antigens of any common bacteria). They "anger" the immune system, making it more aggressive. The adjuvant will work most effectively, being close to the antigen of cancer cells, therefore their joint delivery is necessary (which is achieved by placing the antigen and the adjuvant in the same carrier).

How else can nanocarriers help? For example, to increase the efficiency of antigen presentation by antigen-presenting cells, which will enhance the activation of T cells. Synthetic particles with the drug can enter the lymphoid tissue, where they persist for a long time, gradually releasing antigens and adjuvants. Particle size is one of the key factors determining the effectiveness of their entry into lymphoid tissue [1]. Large particles (more than 500 nm in diameter) are delayed in the injection zone due to their size, and very small (less than 10 nm in diameter) can quickly diffuse through the lymph nodes, which minimizes the possibility of effective interaction of a sufficient number of vaccine particles with antigen-presenting cells [18]. Medium-sized particles (10-100 nm in diameter) reach the lymph nodes and stay there – then the chance of presenting the desired antigen increases significantly [18, 19]. According to the conducted studies, particles with a diameter of 40 nm are considered the best [20]*.

* – When the size of artificial particles becomes comparable to the size of a cell or its individual components, we are talking about the interface of nano–bio – the area of contact between living matter and foreign objects of similar and smaller sizes [4]. Based on the idea of such an interface, various targeted delivery strategies can be built – starting from transdermal [21] and ending with the distribution of nanoparticles between various organs and organelles inside the cell. – Ed.

Let's say scientists managed to deliver the antigen to the right part of the lymphoid tissue. There antigen-presenting cells (preferably dendritic) should interact with it. The surface of nanoparticles carrying cancer antigens can be modified so that dendritic cells bind to it better [1], which will strengthen the immune response. They use different ways to attract DC; interestingly, many of them eventually cause a similar immune response [22].

As mentioned earlier, an important advantage of drug delivery using nanoparticles is the ability to deliver an antigen together with an adjuvant, which enhances the immune response. Substances activating Toll-like receptors (TLR) are recognized as good adjuvants for anti–cancer vaccines [23] - an important component of innate immunity, for the discovery of which the 2011 Nobel Prize was awarded [5]. TLRs sense dangerous pathogenic signals and are primarily involved in the innate immune system. Interestingly, they also play a key role in the induction of acquired immunity [24], and therefore substances that activate them are widely used in vaccines. For example, such a substance is an oligonucleotide containing an unmethylated CpG motif. It carries a negative charge, and it is easy to attach it to positively charged particles [25, 26], which increases the immune response.

Delivery of whole cell-based vaccinesThe advantages of vaccines consisting of whole cancer cells over those consisting of single proteins is that a multi-sided immune response can be achieved [1].

The spectrum of antigens in the whole cell is as high as possible – it contains all potentially immunogenic molecules. The approach can be applied even for individual therapy if the vaccines are made from the patient's cells. Destroyed or inactivated cancer cells are used to obtain the drug. They can also be packaged in synthetic carriers together with activators of Toll-like receptors [27, 28]. For example, particles containing destroyed cancer cells, a factor attracting dendritic cells, and a CpG-containing oligonucleotide for their activation were obtained [29]. This design has successfully ensured the emergence of adaptive anti-cancer immunity and has shown both preventive and therapeutic effects.

New horizons in cancer immunotherapy may open up after the identification of new antigens unique to each patient by sequencing [30]. This approach can significantly increase the effectiveness of treatment, because mutated proteins, which are not present in normal cells, but are present in cancer cells, cause a strong immune response. It may also be effective to use several immunostimulating approaches simultaneously [1].

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19.11.2015
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