CAR-T cell therapy

for leukemia and lymphoma in patients aged from six months to 30 years

Basics of CAR-T Therapy

Modern medicine strives to find more and more effective treatments for oncological diseases. One of the promising areas is cellular immunotherapy, in particular, CAR-T cell therapy. This type of treatment is based on the use of a person’s own T-lymphocytes, “reprogrammed” against tumor cells in the body. These cells act selectively, that is, they are aimed at destroying only tumor cells. This advantage distinguishes CAR-T therapy from other methods, such as chemotherapy, radiation therapy, and surgery. CAR-T cell treatment is innovative and gives a chance for life to patients with leukemia and lymphomas who have exhausted standard therapeutic protocols.

In 2018, the CAR-T therapy method was named the breakthrough of the year in the United States [ 1 ]. At the same time, the FDA (the federal agency that controls the use of drugs in the United States) approved an anti-CD19 CAR-T cell product for the treatment of leukemia, and then lymphoma under the trade name “Kymriah”. The cost of treatment using the new technology was almost $ 500,000 per injection! The cost in the United States and Europe remains high to this day.

The staff of the Center for Children’s Oncology, Hematology and Immunology continued to work on the development of CAR-T cell production technology and clinical protocols for patient management. An important task was to reduce the cost multiple times so that the technology would become more accessible for use.

Who can benefit from CAR T cell therapy?

Currently, the CAR-T cell therapy method is approved by the Ministry of Health of the Republic of Belarus for the treatment of relapsed/refractory forms of CD19+ B-cell lymphoblastic leukemia and lymphomas in children and adults.

Conservative treatment methods used at the Center for Children’s Oncology, Hematology and Immunology make it possible to cure acute lymphoblastic leukemia in most children: the overall survival rate reaches 94%. According to these indicators, the Republic of Belarus is among the best countries in the world. Unfortunately, 15-20% of patients experience a relapse of the disease, and for some of them, protocol anti-relapse therapy is ineffective. It is these patients, who have exhausted all therapeutic options in the treatment of a relapse of the disease, who are given another chance – CAR-T therapy.

Principle of the method

The material for obtaining CAR-T cells is the patient’s own white blood cells, which are collected during hardware apheresis. T-lymphocytes are isolated from the obtained cell fraction in the laboratory, their division is activated, and then modified by introducing an artificial chimeric antigen receptor (CAR). Next, CAR-T cells are grown in a nutrient medium until they accumulate in the required dose. The finished CAR-T cells are returned to the patient by intravenous infusion.

Function of CAR-T cells

Chimeric antigen receptor T cells are able to recognize a specific protein, CD19, present on the surface of tumor cells of B-cell leukemia or lymphoma. CAR-T lymphocytes, circulating in the blood, enter the bone marrow and other organs of the patient, purposefully destroying tumor cells there. It is worth noting that the CD19 protein is also found on the surface of normal B lymphocytes, so one of the side effects of CAR-T therapy is transient B-cell aplasia, which is corrected by replacement therapy with intravenous immunoglobulin.

Preparation and stages of CAR-T therapy

Before prescribing cell therapy, the team of specialists at the Center for Children’s Oncology, Hematology and Immunology must thoroughly familiarize themselves with each case of the disease. To do this, it is necessary to send medical documentation to e-mail: oncology.by@gmail.com with the obligatory indication of the phone number for feedback and citizenship (residence permit in the Republic of Belarus) of the patient.

If the indications for CAR-T therapy are confirmed, a contract for the provision of medical services is concluded. The contract is concluded in person, that is, the immediate presence of the patient or, in the case of minors, his parent or legal guardian is required. This period will not take more than two days, and we will provide comfortable conditions for the patient and accompanying person to live on the territory of the clinic.

After the conclusion of the contract, preparation for the procedure is carried out in stages, each stage is accompanied by serious work of medical personnel and observation in a hospital setting and, if necessary, in an intensive care unit:

Stage 1: leukapheresis or the sequential process of collecting and isolating lymphocytes from the blood. At this stage, the patient is connected to a special device for collecting lymphocytes from venous blood. The procedure takes up to 4 hours, after which the obtained lymphocytes are sent to the laboratory.

Stage 2: obtaining CAR-T cells. The patient’s participation is not required at this stage. CAR-T cells are obtained in the laboratory. In this case, T-lymphocytes are isolated from the apheresis product, modified, grown and prepared for administration to the patient. The entire process takes 10-14 days, but if necessary, CAR-T cells can be frozen and stored for a longer period.

Stage 3: preparing the patient for the introduction of CAR-T cells. After a comprehensive diagnosis and examination, the patient undergoes a special course of chemotherapy called lymphodepletion. It is necessary to reduce the number of leukocytes in the blood and, accordingly, reduce both the risk of rejection of CAR-T cells and prevent complications from the immune system. From stage 1 to stage 4, the duration of therapy is about 2 weeks.

Step 4: CAR-T cells are administered intravenously, the infusion duration is about 30 minutes.

Stage 5: Monitoring the patient’s condition and side effects. After the modified cells enter the blood, they are distributed throughout the body, directed to tumor cells, recognized and destroyed. This is the most difficult stage for the patient, but the medical team has sufficient experience and equipment to cope with side effects. It is important for the patient to understand that there is a struggle between good and evil in the body, in which side effects of varying degrees of severity are the norm and the price of victory over the disease. The critical period, requiring constant clinical monitoring and accompanying therapy, is about a month. It is very important that the patient is monitored during this period and, if necessary, provided with qualified medical care. The doctor assesses the patient’s condition, adjusts drug treatment if necessary. After the condition has normalized and the patient has undergone follow-up examinations, he or she is discharged and given further recommendations.

Side effects of CAR-T therapy.

1. Cytokine release syndrome (CRS).Occurs as a result of the activation and proliferation of CAR-T cells, which leads to excessive cytokine production by a number of immune cells and an increase in the systemic inflammatory response. These reactions are naturally associated with the work of antitumor immunity, and their occurrence is inevitable. Cytokine release syndrome is observed in 74-100% of cases after the introduction of a cellular product. It most often develops in the period from 3 to 12 days after the introduction of CAR-T cells. Clinical symptoms can vary from mild (fever, muscle pain, weakness, decreased blood pressure) to severe, requiring intensive care. Early recognition of the signs of a cytokine storm allows you to cope with it more effectively.
2. Neurotoxicity, also known as CAR-T-associated neurotoxicity syndrome (ICANS), occurs less frequently, with an incidence of 2 to 45%. Neurological symptoms most often manifest as confusion, toxic encephalopathy, tremors or seizures, and speech impairment. Mild to moderate neurotoxicity is the most common. These side effects are also preventable and treatable.
3. Infections. As a result of previous chemotherapy and side effects of CAR-T therapy itself, the patient has leukopenia, lymphopenia, and absence of B cells, which predispose him to the development of infectious complications. In this regard, the patient must be under the supervision of a hospital physician for timely treatment of emerging complications until they are completely resolved.

Carrying out the CAR-T therapy procedure at the Center for Children’s Oncology, Hematology and Immunology

Thanks to the powerful scientific and technical base and the latest developments of the Center for Children’s Oncology, Hematology and Immunology, this method is actively used in the Republic of Belarus in patients with relapsed/refractory forms of CD19+ B-cell leukemia and lymphoma . Treatment at the Center for Children’s Oncology, Hematology and Immunology is available not only to children under 18, but also to young adult patients under 30. The method has been successfully used since 2020.

CAR-T cell therapy shows promising results in patients with chemotherapy-resistant tumors. More than 80% of patients diagnosed with refractory or relapsed B-cell lymphoblastic leukemia achieve remission. CAR-T therapy does not guarantee a 100% cure or long-term remission. For this reason, researchers around the world are trying to conduct CAR-T in combination with other treatment options, primarily in combination with allogeneic hematopoietic stem cell transplantation . This combination of treatments can significantly increase the chances of a cure.

Cost of Treatment

No.	Types of medical services	Quantity	Price for service, USD	Total amount, USD	Total amount, RUB	Total amount, BYN
1	Comprehensive patient examination (assessment of patient status for the need for CAR-T therapy)			5000,00	432133,00	15600,00
2	Lymphocyte collection (leukapheresis)			467,50	40409,50	1458,78
3	Provision of medical services for obtaining CAR-T cells (for patients weighing less than 40 kg)			17591,00	1520330,50	54883.93
3.1	Provision of medical services for obtaining CAR-T cells (for patients weighing over 40 kg)			21506,50	1858752,50	67100,97
4	Carrying out CAR-T therapy to a patient, including:			24326,00	2102413,00	75897,10
4.1	stay in the day care department (bed days)	12		308.92	26 699,17	963.84
4.2	stay in the department of anesthesiology and intensive care (bed days)	3	246.16	738.48	63824,38	2304.06
4.3	inpatient treatment	20	101.37	2027.44	175224,38	6325,60
4.4	Laboratory diagnostic tests			15400,00	1330969,79	48048,00
4.5	Medicines and consumables			5851,16	505695.29	18255,60
	Total (for patients weighing less than 40 kg)			47384,50	4095286,00	147839,81
	Total (for patients weighing over 40 kg)			51300,00	4433708,00	160056,85

*_{the cost of the service in US dollars and Russian rubles is determined at the time of the conclusion of the agreement at the exchange rate of the National Bank of the Republic of Belarus}

The cost of CAR-T therapy is not fixed and may change during treatment depending on the severity of the patient’s condition and the scope of the necessary examination. In case of a reduction in the cost of treatment, the Center guarantees a refund.

Note: if there is a need to repeat medical services for obtaining CAR-T cells, a discount of 15% of the cost of the work is provided (excluding the cost of materials).

Get a consultation

by e-mail : oncology.by@gmail.com

Single number for residents of near and far abroad (Russia, Kyrgyzstan, Kazakhstan, Uzbekistan, etc.) Viber, WhatsApp, Telegram : +375 29 838-40-46

with the obligatory indication of the phone number for feedback and citizenship (residence permit in the Republic of Belarus) of the patient. The full list of services can be found on the website oncology.by.

Coordinator of the Department of Extra-budgetary Activities, Research Associate of the Clinical Research Laboratory of the Scientific Department Olga Andreevna Mishkova.

Sources of information:

[1] https://pubmed.ncbi.nlm.nih.gov/29380678/