CAR T-Cell Therapy: A Healthcare Professional's Guide - The Top Questions Answered
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on Aug 19, 2021.
What is CAR T cell therapy?
Chimeric antigen receptor (CAR) T-cell therapy is a new, technologically advanced form of cancer treatment now approved by the FDA. This personalized therapy is engineered from a patient's own white blood cells (T-lymphocytes) to actively search for antigens and destroy cancer cells in patients failing other treatment options. Approved therapies include:
- Kymriah (tisagenlecleucel) from Novartis is approved for certain pediatric and young adult patients with acute lymphoblastic leukemia (ALL). It received approval in May 2018 for large b-cell lymphoma in adults.
- Yescarta (axicabtagene ciloleucel), from Gilead, was given the go-ahead to treat adults with large B-cell lymphoma in the fall of 2017 and for indolent follicular lymphoma in March 2021. These are two types of non-Hodgkin lymphoma.
- In July 2020, Kite's Tecartus (brexucabtagene autoleucel) was approved as the first CAR T treatment for relapsed or refractory mantle cell lymphoma in adults.
- In Feb 2021, Breyanzi (lisocabtagene maraleucel) from Juno Therapeutics was cleared to treat large B-cell lymphoma in adults.
- Abecma (idecabtagene vicleucel) from Bristol-Myers Squibb was OK'd for treatment of multiple myeloma in adults in March 2021.
CAR T-cell therapy is not a "drug" in the usual sense, as might be used in chemotherapy. Instead, it is a living biologic created from a patient's own cells. T-cells normally target cancer cells, but aren't always as efficient as they should be, and the rebuilt CAR T-cells can help to boost their cancer-killing ability.
Which cancers are treated with CAR T?
- Aggressive B-cell non-Hodgkin lymphoma (diffuse large b-cell lymphoma, primary mediastinal b-cell lymphoma, and transformed follicular lymphoma)
- Relapsed/Refractory Mantle Cell Lymphoma
- Chronic Lymphocytic Leukemia
- Young adult and Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia
- Multiple myeloma
- Indolent Follicular Lymphoma
When was CAR T-cell therapy first approved?
On August 30, 2017, the FDA approved Kymriah (tisagenlecleucel), the first U.S. CAR-T cell therapy, for pediatric and young adult acute B-cell acute lymphoblastic leukemia (ALL).
The second available CAR T agent, Kite/Gilead's Yescarta (axicabtagene ciloleucel), also previously known as KTE-C19, was approved on October 18, 2017.
Since then, Tecartus (brexucabtagene autoleucel), Breyanzi (lisocabtagene maraleucel) and Abecma (idecabtagene vicleucel) have cleared the FDA for CAR T cell treatment in various advanced cancers failing other treatments.
Learn more: FDA Approval History and Pivotal Studies
How is CAR T cell therapy given?
CAR T therapy is manufactured specifically for each individual patient. CAR T-cell therapy is a biologic-type of living drug which involves a personalized procedure, unlike taking a daily pill or receiving several rounds of chemotherapy.
The receipt of CAR T cell therapy is a one-time procedure, and the CAR-T cells may continue to replicate to fight the cancer in the body. But side effects can be challenging and serious. Here's the general process:
- Apheresis, a procedure to collect the patient's white blood cells (lymphocytes) is performed in the hospital. Then the T-cells are isolated.
- The T-cells are sent to lab where they are genetically engineered to construct a chimeric antigen receptor (CAR) on the cell surface. Genes are inserted into the T-cells using an inactive virus which allows the CAR T-cell to activate, recognize, and kill the cancer cell.
- The tumor antigen, such as CD19 or B-cell maturation antigen (BCMA), are proteins on the surface of cancer cells. Different cancers have different antigens, and CAR T is specific for these antigens.
- The CAR T-cell is grown in the lab for roughly 2 weeks to multiply the T cells by the hundreds of millions. The cells are frozen and then sent to the hospital for re-infusion to the patient.
- In the mean time, the patient has received conditioning chemotherapy to help lower the white blood cell count and allow the CAR T-cells to be better accepted.
- The reengineered CAR T-cell is then infused back into the patient to find the specific cancer antigen, bind to it, and lead to the death of the antigen-expressing cancer cell.
What are the side effects with CAR T-cell therapy?
CAR T-cell therapy is used in patients with high tumor burden and advanced disease; these patients have run out of treatment options. But side effects of CAR T-cell therapy can be daunting. Ironically, some of the adverse events are due to cytokine release because the patient is having a positive response to therapy. The most commonly reported adverse effects seen in CAR T-cell therapy clinical trials include:
- Cytokine Release Syndrome (CRS): Very high fevers, sharp drops in blood pressure, tachycardia, and low oxygenation can occur, usually in the first week. Administration of tocilizumab (Actmera), an agent that blocks IL-6, is approved to manage cases of CRS.
- Neurotoxicity: May include delirium, confusion, somnolence, agitation, delirium, ataxia, aphasia, and seizure.
- B-Cell Aplasia: B cell aplasia is defined as low or absent B cells (a type of white blood cell) and is an expected side effect of CAR T cell therapy that can boost infection risk; monthly intravenous immunoglobulin (Ig) infusions help manage this side effect.
- Tumor-Lysis Syndrome (TLS): Another expected side effect; TLS occurs due to cell death and subsequent release of contents into the bloodstream; metabolic, electrolyte and possible organ failure complications ensue; management is standard supportive therapy.
- Cerebral Edema: Can be fatal; at least eight cerebral edema-related deaths have been reported.
How Much Does CAR T-Cell Therapy Cost?
A personalized and complicated engineering process such as CAR T cell development is expected to be costly.
- Kymriah, the first CAR-T cell therapy approval, is roughly $475,000 per treatment.
- The cost of Kite/Gilead's Yescarta is estmated at $373,000 per treatment regimen.
- Abecma, approved in 2021 for multiple myeloma and the first B-cell maturation antigen (BCMA) CAR T, costs around $437,968 for the single treatment.
What other factors push up the cost of CAR T? Specialized facilities and healthcare providers, manufacturing costs, possible need for intensive care post-infusion due to serious adverse events, prolonged hospitalization or the need to stay close to the facility for follow-up all magnify the overall cost.
Does CAR T Cell Therapy Work in Solid Tumors?
Utilizing traditional CAR T-cell therapy to treat solid tumors is actively under research but proves challenging, often due to:
- an inhospitable solid tumor microenvironment (oxidative stress, lack of nutrients, an acidic pH).
- heterogenous antigens.
- the presence of immunosuppresive pathways like immune checkpoint.
Studies are ongoing at large, state-of-the-art treatment centers such as MD Anderson in Houston. They are conducting studies in solid tumors such as breast cancer, lung cancer, pancreatic cancer and prostate cancer.
T-cell receptor, or TCR, may be able to target a wide range of solid tumors. Like CAR T-cell therapy, TCR therapy yields tumor apoptosis and programmed cell death, can expand T-cells numbers, and results in circulation throughout the body to target distant cancer cells.
Natural Killer T-cells (NKTs) are another type of white blood cell being researched in solid tumors. For example, CAR-NKTs are being researched to treat neuroblastoma solid tumors that grow in nerve cells outside the brain and occurs most frequently in infants and young children. NKTs can populate neuroblastoma tumors and attack the cancer cell and the cells that encourage tumor growth.
Tumor-infiltrating lymphocytes (TILs) are another cell therapy type being researched to treat melanoma.
Is There A Universal CAR-T Cell Therapy?
Creating a universal CAR T agent could help avoid the lengthy and sometimes dangerous time period from apheresis of T-cells to re-infusion, which on average runs 2 to 2.5 weeks, although these timelines are expected to get shorter.
"Off-the-shelf" or "universal" T-cell therapy (allogenic) CAR T-cell production is under research. While personalized CAR T-cell therapy developed from the patient's own T-cells is best to limit any potential graft-versus-host-disease (GVHD), some patients cannot wait for the development of their own personalized product. Some patients may be too sick to wait for production, or some cannot tolerate apheresis at all.
Research is ongoing to develop this "off-the-shelf" technology; however, it still remains to be seen if allogeneic "off-the-shelf" T-cell products will be as robust as autologous CAR T-cell therapies. According to one review, advances in genome editing tools, for example via CRISPR technology, could help to overcome the two main limitations of allogeneic CAR T cells product -- GVDH and host allorejection.
Finished: CAR T-Cell Therapy: A Healthcare Professional's Guide - The Top Questions: Answered
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- Clarke T, et al. FDA approves Gilead cancer gene therapy; price set at $373,000. Reuters. Healthcare and Pharma. October 18, 2017. https://www.reuters.com/article/us-gilead-sciences-fda-idUSKBN1CN35H
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