Methods of immuno-oncotherapy
Cell Wars: a new Hope
Daria Spasskaya, N+1
The main theme of the new issue of the magazine Cancer immunotherapy has become Science – a group of new approaches in the treatment of malignant tumors, the development of which is now focused on a significant part of the efforts of researchers.
In this issue, leading experts in the field of immunotherapy have published reviews of research in the field of "checkpoint" therapy, cancer vaccines, as well as a review on the problems in the creation of lymphocytes with chimeric antigen receptors (CAR-T). We asked Alexey Kuzmich, a researcher at the Gene Immunotherapy group of the Institute of Bioorganic Chemistry of the Russian Academy of Sciences, to tell us what cancer immunotherapy is, what areas it includes, and why scientists have such high hopes for it.
Traditional methods of cancer treatment – chemo or radiation therapy – is an attempt by "external means" to destroy actively dividing tumor cells. The task of immunotherapy, which includes a whole group of methods, is to make the patient's immune system engage in this war itself.
In a sense, immunotherapy is a "natural" method of treating malignant diseases. The fact is that malignant cells are constantly formed in the human body due to natural processes (mainly replication errors during division), but thanks to the work of the immune system, they are recognized and destroyed in a timely manner. If the immune system weakens (for example, with age) or mutant cells find a way to deceive it, the balance is disturbed and cancer occurs. Immunotherapy is a way to restore balance.
The results demonstrated by certain immunopreparations in the clinic in recent years look encouraging. Most traditional chemotherapeutic drugs work successfully at the beginning of treatment, but after a while the tumor cells develop resistance to them, and the disease returns. In the case of immunotherapy, many patients show complete and prolonged remission, and often in advanced cases when metastases have spread throughout the body. In addition, immunotherapy sometimes works when other treatments have stopped working (or have not worked at all).
It is possible to distinguish such areas of immunotherapy:
Anti–cancer vaccines - substances produced by cancer cells are injected into the body in order to develop a specific immune response to them.
Immune modulators (cytokine therapy) – signaling proteins or growth factors are introduced into the body, which increase the number of immune cells and their activity in general.
Checkpoint inhibitors (or immune checkpoint inhibitors) are compounds (usually monoclonal antibodies) that inhibit the activity of immune checkpoints.
Let's explain in more detail how the latter method works. On the surface of immune cells there are receptors – the so-called immune checkpoints ("checkpoints", from the English checkpoint), the activation of which suppresses the development of the immune response. These are, in particular, PD-1 and CTLA4 proteins. Suppression is necessary to prevent excessive activation of immunity and the development of autoimmune diseases.
Tumor cells have learned to use these receptors to avoid an attack by the immune system. They produce large amounts of protein activators that recognize these receptors and suppress the immune system. Checkpoint inhibitors bind to these activators or receptors, block them and thus prevent tumor cells from escaping an immune reaction.
The fourth direction is cellular immunotherapy. In this case, immune cells are extracted from the body, "trained" in a test tube to recognize (or represent) targets on the surface of tumor cells, and then injected into the patient, where they form an antitumor immune response. This group includes CAR-T therapy and therapy with trained antigen-presenting cells. CAR-T, that is, lymphocytes with chimeric antigen receptors, have a number of advantages: it is a highly specific therapy, with the use of which there is a possibility of complete destruction of all cells carrying tumor antigen – this can lead to the patient's cure even if other treatments have proved powerless. Such lymphocytes can remain in the blood for a long time and maintain a therapeutic effect. (In the USA, two CAR-T–based drugs against various forms of leukemia have been approved over the past year - ed.).
Of course, even the most promising drugs have not only pros, but also cons. For example, not all types of tumors respond well to therapy with checkpoint inhibitors. At the same time, no clear prognostic markers of the effectiveness of such treatment have yet been found (it is impossible to understand with the help of analyzes who should be given such drugs and who should not). These drugs are expensive. A serious limitation is the high frequency of side effects associated with an attack by the immune system of normal tissues. A large number of checkpoint inhibitor combinations with other therapies are currently being tested. Apparently, such combinations can show good synergy – for example, radiotherapy leads to the death of tumor cells, which attracts immune cells to the tumor, and checkpoint inhibitors help overcome the suppression of the immune system and attack the surviving tumor cells.
The disadvantages of cellular immunotherapy primarily include a dangerous side effect caused by a "cytokine storm", that is, the simultaneous release of a large number of inflammatory mediators. It can even lead to the death of the patient. In addition, normal cells with a target marker on the surface are also attacked. So, after CAR-T therapy of lymphoma, B-cells are destroyed in the body, so patients after treatment are forced to regularly receive antibodies to protect against infections. CAR-T have performed well in the treatment of blood cancer, but their effectiveness against solid (solid) tumors is questioned. The reason for this is the high heterogeneity of cells in such tumors and difficult access to tumor tissue. In addition, this therapy is very expensive – for the first approved drugs, the cost of the course is hundreds of thousands of dollars.
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