What is the CAR-T treatment process? How should patients and families work with their doctors to receive treatment?
There are 4 major steps in the CAR-T cell therapy process:
Step 1: Extraction of patient T cells
Patients’ peripheral venous blood is collected in 60-100 ml, and 100 ml contains about (2-3) × 10 single nucleated cells, which are isolated and purified in vitro. Then the purified T cells were made to express chimeric antigen receptor (CAR) by lentiviral transduction and other means, which became CAR-T cells.
Step 2: In vitro preparation of specific CAR-T cells
After culture to get the expansion to reach the number of cells for transfusion; strict quality control and strict aseptic operation to ensure that the prepared CAR-T cells can be used for clinical treatment.
Step 3: Pretreatment chemotherapy before CAR-T treatment
Patients receive appropriate chemotherapy prior to cell therapy to reduce the number of tumor cells in the body and to “clear the lymph”. Chemotherapy will begin 5 to 10 days before the return of the anti-CD19 CAR-T cells, which in turn will ensure that chemotherapy is completed 1-2 days before the return.
Step 4: CAR-T cell transfusion
Prepared CAR-T cells are infused back to the patient using a single dose or fractionated infusion. At the end of the infusion, a checkup is performed at a defined time assessment point to evaluate efficacy and toxic side effects.
Because CAR-T cell therapy can lead to toxic side effects such as cytokine storm and neurotoxicity, which can be life-threatening. To minimize the occurrence of these adverse events, patients and their families need to be familiar with CAR-T therapy and the toxic side effects that occur before CAR-T cell therapy is administered, and they need to understand and cooperate with CAR-T cell infusion because frequent blood collection and other tests are needed to monitor the extent of toxic side effects.
After CAR-T cell infusion, many patients experience persistent high fever and diarrhea, which requires careful care from the patient’s family in addition to the usual care by nurses. And, because the early signs and symptoms of cytokine storm and neurotoxicity are more easily recognized by these family members who know the patient best, they also need to be able to stay with the patient full time during CAR-T treatment. Any new symptoms, such as shortness of breath, abdominal pain, headache, vision changes, and/or mood changes, should be communicated to medical staff within the first hour.
Why is pretreatment chemotherapy given before CAR-T treatment? What are the common pretreatment regimens?
Patients currently receiving CAR-T cell therapy are often patients with advanced tumors and high tumor loads, which can be reduced by pretreatment chemotherapy; on the other hand, pretreatment chemotherapy can be used to “clear the lymphocytes”, that is, to remove lymphocytes from the patient’s body to promote the return of CAR-T cells to be able to expand and survive in the patient’s body. The patient’s lymphocytes can be removed from the patient’s body to facilitate the expansion and survival of the infused CAR-T cells.
The FC regimen (fludarabine 25-30 mg/m; cyclophosphamide 250-300 mg/m by IV infusion for 3 d) is now commonly used as a pretreatment regimen.
How can CAR-T therapy ensure adequate cell collection in many patients with poor bone marrow function after long-term chemoradiotherapy?
Most centers are using peripheral therapy.
Most centers use peripheral mononuclearcell (MNC) mono-collection to ensure that enough immune cells are collected, but patients need to have a peripheral platelet count ≥50×10/L and good peripheral vascular status. For patients with low platelets who cannot undergo mono-collection, CAR-T cells are prepared at our center (Department of Hematology, Shanghai Tongji Hospital) by collecting 50-100 ml of blood from peripheral blood (the preparation process is patented), and the number of cells prepared can be 1-10×10/kg, which is sufficient for the current number of CAR-T cells for the treatment of acute leukemia and lymphoma.
How long should the CAR-T treatment cycle be? Does it require long-term maintenance? Do you have to be hospitalized all the time during treatment?
The CAR-T cell treatment cycle often takes about a month.
CAR-T cells are infused back within 1 to 2 days after the end of pretreatment chemotherapy with the FC regimen (fludarabine + cyclophosphamide), either in 1 infusion or in 2 to 3 infusions to reduce side effects. The cell infusion is often completed in 15-30 minutes, after which the efficacy and side effects are observed and monitored. Because the side effects of CAR-T cell therapy often begin within a week of the cell infusion and peak within 1 to 2 weeks. Therefore, patients need to be hospitalized for observation during this period so that they can receive timely management and specialized treatment by health care providers if toxic side effects occur.
Is it necessary to do multiple infusions of CAR-T? Do I need regular gammaglobulin?
Current CAR-T cell therapies for the same target often require only a single infusion. CAR-T cell therapy against the B-cell tumor antigen CD19 often results in an On target/off tumor effect, i.e., B-cell depletion, which leads to hypoimmunoglobulinemia and needs to be supplemented by regular gammaglobulin infusions (usually once every 2 to 3 months).