Chimeric antigen receptor (CAR) T-cell therapy is a novel immunotherapy that uses the body’s own immune system to target cancer cells. The therapy involves engineering the body’s T-cells to produce synthetic molecules on their surface — called chimeric receptors — that can specifically recognize and attack cancer cells. The receptors can be modified depending on the type of cancer cell being targeted.
The U.S. Food and Drug Administration (FDA) has approved two CAR T-cell therapies: Kymriah (tisagenlecleucel) for the treatment of acute lymphoblastic leukemia (ALL), and Yescarta (axicabtagene ciloleucel) for the treatment of diffuse large B-cell lymphoma (DLBCL). CAR T-cell therapies also are being investigated as a potential treatment for myeloma.
How does CAR T-cell therapy work?
CAR T-cell production is a multi-step process. The T-cells required for CAR T-cell therapy can be taken either from the patients themselves — called autologous treatment — or from a compatible donor, known as allogeneic therapy.
The first step is to harvest T-cells from the patient or donor. Blood is collected and passed through an apheresis device to separate out the T-cells, with the remaining blood returned to the person’s body. The collected T-cells are then sent to the laboratory for engineering.
In the laboratory, the T-cells are edited genetically. Harmless viruses are used to introduce DNA that would help the T-cells in making the appropriate CARs on their surface. These CARs help in recognizing the cancer cells and direct the T-cells specifically toward them. Each CAR T-cell therapy is unique and can have a different manufacturing process.
These engineered T-cells are now called CAR T-cells. They are multiplied in the laboratory to create a sizeable population and frozen for transport back to the clinic.
CAR T-cell infusion
Before receiving the CAR T-cells infusion, the patient must undergo a conditioning regimen called lymphodepletion. This procedure, which uses chemotherapy drugs such as fludarabine and cyclophosphamide, helps reduce the normal lymphocyte, or white blood cells count that could otherwise potentially hinder the activity of the new CAR T-cells.
Once in the patient’s body, the CAR T-cells further multiply and differentiate into several T-cell subtypes depending on how they were designed.
The CAR T-cells destroy the cancer cells in the patient’s body. They remain active from 30 days to four years after administration. During this time, they continue to seek out and target cancer cells, and hence are called “living drugs“.
CAR T-cells in multiple myeloma
CAR T-cells are being explored in clinical trials as an immunotherapy option for treating myeloma. Myeloma cells — or B-cells that grow uncontrollably in myeloma — produce a protein called B-cell maturation antigen (BCMA). CAR T-cells engineered to detect this protein can target these myeloma cells and destroy them.
A more recent development is the use of a dual CAR T-cell combination for the treatment of myeloma. In this approach, patients are infused with both the CAR T-cells that produce BCMA and with those engineered to target certain forms of B-cells that produce the CD19 protein.
The strategy here is that, even with the reduction of myeloma cell population via anti-BCMA CAR T-cells, there still could be B-cells that would eventually become cancerous over time. Targeting them using anti-CD19 CAR T-cells could prevent a relapse of the cancer.
CAR T-cells in clinical trials
Owing to their immense potential, CAR T-cells are the subject of many clinical trials.
A Phase 1/2 clinical trial (NCT03018405) called THINK is assessing the safety and efficacy of escalating doses of autologous NKR-2 CAR T-cells in the treatment of different types of cancer, including multiple myeloma. The trial is currently recruiting and expects to enroll an estimated 146 patients in the U.S. and Belgium. THINK is expected to be completed in August 2021.
A Phase 1 dose-escalation and dose-expansion clinical trial (NCT02658929) is studying the adverse events and outcomes of bb2121. This anti-BCMA CAR T-cell therapy was developed by Celgene for the treatment of relapsed or refractory multiple myeloma (RRMM). The trial, involving 67 participants in the U.S., is ongoing and expected to be completed in November 2023.
The initial results indicated that the adverse events were very manageable, with high response rates and about 45% of patients showing a complete response.
Another Phase 1 dose-escalation clinical trial (NCT03464916) aims to evaluate the safety and efficacy of the CAR2 anti-CD38 CAR-T cell therapy developed by Sorrento Therapeutics for the treatment of RRMM. This trial is currently recruiting an estimated 72 participants in the U.S. and is expected to be completed in September 2020.
In China, a single-center Phase 1 clinical trial (NCT03751293) is currently recruiting 10 participants. The trial will test the safety and efficacy of an anti-BCMA CAR T-cell therapy called C-CAR088 for the treatment of RRMM. It is expected to be completed in October 2020.
A Phase 2 clinical trial (NCT03361748) called KarMMA aims to study the safety and efficacy of bb2121 CAR T-cell therapy in RRMM patients. The trial is currently recruiting patients across the U.S., Canada, Europe, and Japan, and is expected to be completed in November 2024.
CAR T-cell therapy can cause several side effects, including cytokine-release syndrome (CRS), macrophage activation syndrome (MAS), and tumor lysis syndrome (TLS). It also can lead to anaphylaxis, which is a life-threatening allergic reaction, on-target off-tumor toxicity, B-cell aplasia — low numbers of B-cells — and neurologic toxicities such as confusion and seizures. A limited number of CAR T-cell trials also have shown instances of cerebral edema, a life-threatening condition that develops as a result of an inflammatory reaction.
Anti-inflammatory treatments such as Actemra (tocilizumab) have been approved by the FDA to manage CRS symptoms. Off-target effects such as B-cell aplasia can be managed by immunoglobulin replacement therapy to help fight infections.
Last updated: Dec. 3, 2019
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