The idea of using immunity mechanisms to fight malignant diseases has been around for more than a hundred years now. It has long been known that there are special cells in the human body – T lymphocytes, NK cells and macrophages – which are able to recognize and destroy pathologically altered tumor cells.
For a long time, scientists have tried to understand why antitumor immunity did not work well enough and tried to find ways to strengthen it. In recent years, it has become clear that many tumors have mechanisms protecting them against the effects of cells of the immune system and that malignant cells differ little in their immunological properties from normal cells, making it difficult for the immune cells to recognize them. The first problem was partially solved with the appearance of inhibitors, the so-called control points-proteins, by which tumor cells suppress the activation of T lymphocytes. One of such protein is PD-L1. PD-1/PD-L1 inhibitors revolutionized the treatment of patients with intractable skin tumor – melanoma. However, this approach has not been effective in treating all types of tumors.
The development of CAR T cells – one of the types of cell therapy, which combines the latest advancement of molecular biology, genetic engineering and biotechnology – helps in making tumor cells more visible to the immune system.
CAR T (chimeric antigen receptor-T) cells are patient's T lymphocytes isolated from their own blood, genetically modified and then multiplied many times in sterile laboratory conditions. As a result of genetic modification, the cells (T lymphocytes) begin to produce an artificial protein (chimeric antigen receptor), which has an affinity for a specific target protein (antigen) on the surface of tumor cells. With the help of chimeric antigen receptors, T lymphocytes acquire the ability to recognize tumor cells and selectively attack them. One CAR T cell may in turn destroy some tumor cells. Moreover, the CAR T cells after activation, divide, resulting in the increase of the number of the CAR T cells in the blood, that is to say, there is an amplification of the antitumor effect. Some CAR T cells can persist in the patient's body for more than a year providing reliable antitumor immunity – protection against recurrence of the disease.
Currently, the most widespread cell therapy involves the use of CAR T cells with different types of CD19 protein receptors, marking tumor cells which originated from B lymphocytes and their predecessors (B-acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphomas, chronic lymphocytic leukemia). It was observed in clinical studies that more than half of the patients with chemorefractory variants of these diseases after a single intravenous transfusion of CD19-specific CAR T cells had a long deep remission. At the end of 2017, two types of CD19 CAR T therapy (drugs Kymriah and Yescarta) were first approved for clinical use, however, so far only in the United States.
In Russia, the results of preclinical (in vitro) studies of CD19 CAR T cells were demonstrated for the first time by the specialists of the Institute of Hematology at Almazov Centre on October 26, 2017 at the 14th conference Malignant Lymphomas held in Moscow. The poster “Anti-CD19 CAR-T: the experience in obtaining and initial testing of the product” aroused great interest and was awarded a diploma of the third degree. The poster presented the characteristics of CAR T cells with real therapeutic potential, their ability to destroy CD19-positive cells in vitro, and the ability to divide and secrete biologically active substances (IL-2, TNF, IFNy).
At present, Almazov Centre continues to develop this method of therapy, conduct research aimed at obtaining universal allogeneic CAR T cells and study the resistance mechanisms of other tumors to CAR-T therapy.