CAR-T (chimeric antigen T-cell) therapy is a type of immunotherapy used to treat cancer. The therapy is sometimes known as a type of 'adoptive cell transfer' and is specifically developed for individual patients. The process involves reprogramming a patient's immune system cells, which specialists then use to target their cancer.
CAR-T therapy is relatively new to the regenerative medicine scene. In 2017, the Food and Drug Administration (FDA) approved the first CAR-T therapies. The community site RegMedNet covered this announcement and has published features on the therapies' development and manufacture ever since. RegMedNet provides an online knowledge hub for the regenerative medicine community, where users can access webinars, peer-reviewed journal articles, industry news, and expert insights.
Here, we'll explore how CAR-T therapy works and which patient groups benefit from the treatment.
How Does CAR-T Therapy Work?
To understand CAR-T therapy, it's important to first understand how T cells work. T cells are a type of white blood cell called lymphocytes. Our bodies make T cells when we encounter a new infection or disease (including cancer) to fight that infection or disease. We keep some T cells in reserve once we have recovered in case we come across the infection again. This way, we can attack reoccurring infections.
However, T cells can't always tell the difference between cancer cells and normal cells. So, scientists are developing methods like CAR-T therapy to help T cells recognize cancer cells so they can destroy these. Here's how the therapy works.
1. Collecting the T Cells (Apheresis)
First, a specialist takes a sample of T cells from a cancer patient's blood. The specialist takes the sample by inserting a tube (a cannula or a vascath) into a vein in each of the patient's arms. One tube passes the blood into an apheresis machine, which separates the T cells from the blood. The machine returns the rest of the blood to the patient through the tube in their other arm. This part of the process can take four to five hours.
2. Making CAR-T Cells
A lab team then genetically engineers the T cells, transforming these into CAR-T cells. These cells are much better at recognizing and targeting specific proteins in cancer cells. Lab teams may use one of several expansion platforms and techniques to generate therapeutic doses of CAR-T cells, such as GE or G-Rex bioreactors, the Miltenyi CliniMACS Prodigy system, or recursive AAPC stimulation. It can take a few weeks to generate enough CAR-T cells. When the lab team has enough, they freeze the cells.
3. Chemotherapy
A patient needs to have chemotherapy over a few days before they can have CAR-T therapy. Chemotherapy reduces the number of T cells in the body and prepares a patient to receive the CAR-T cells. This process is called lymphodepletion.
4. Receiving the CAR-T Cells
Once the specialist has defrosted the CAR-T cells and given the patient medicines to reduce the likelihood of allergic reactions, they can feed the CAR-T cells into the patient's bloodstream via a drip. This usually takes less than half an hour. The modified cells can stay in the body for long periods of time, allowing them to attack cancer cells on an ongoing basis. Researchers are still analyzing how long these cells can stay in the body.
5. Hospital Stay
The medical team closely monitors the patient during and after the treatment. The patient stays in a hospital or a nearby residence (funded by the hospital) for two weeks after their therapy. If available, the patient can then visit a day care unit (ambulatory clinic or Ambi-care) every day. If the patient develops medical complications, they will have to stay in hospital for longer. Medical teams usually recommend that patients stay within an hour's drive of the treatment center for up to 28 days after their therapy.
Who Can Have CAR-T Therapy?
CAR-T therapy is available for some children who have leukemia and some adults who have lymphoma. Individuals who have other types of cancer might undergo CAR-T therapy as part of a clinical trial.
Doctors may recommend CAR-T therapy for patients who are 25 or younger and have a type of leukemia called B cell ALL. These patients may:
- Be newly diagnosed children.
- Have undergone two unsuccessful treatment cycles.
- Have relapsed after a bone marrow or stem cell transplant.
- Have relapsed at least twice.
- Have recovered from leukemia, but the cancer has come back, and chemotherapy isn't working.
- Have recovered from leukemia, but the cancer has come back, and they can't have a stem cell transplant because they aren't well enough or because they don't have a donor.
Doctors may also recommend CAR-T therapy for adults who have one of three types of lymphoma: diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, or mantle cell lymphoma. In some patients, the diffuse B cell lymphoma or primary mediastinal lymphoma has grown or relapsed after two or more treatments. In other patients, the mantle cell lymphoma has grown or relapsed after a treatment involving a targeted drug called a Bruton's tyrosine kinase inhibitor.
As patients must fulfill specific criteria to undergo CAR-T therapy, only around 200 adults and a few children undergo the treatment each year.
What Are the Side Effects of CAR-T Therapy?
As CAR-T therapy is a relatively new treatment, doctors might not know about all possible side effects yet. However, known side effects include:
- Allergic reactions to the CAR-T cells. Symptoms of an allergic reaction may include a high temperature, chills, feeling sick, vomiting, and difficulty breathing. Patients take medication before receiving the CAR-T cells to reduce the likelihood of a reaction.
- Neurological changes. CAR-T cells may cause problems in the brain (neurotoxicity). Symptoms may be mild or severe and can include headaches, confusion and disorientation, altered consciousness, speech changes, and seizures. These symptoms might go away on their own, or the patient may need treatment.
- Cytokine-release syndrome. Cytokines are proteins that boost the immune system. CAR-T therapy stimulates the immune system to produce more cytokines, which can cause a patient to experience a fever, dizziness due to low blood pressure, and difficulty breathing. These symptoms can emerge within a couple of weeks of the therapy. Patients can take a treatment for this syndrome, although some patients may need to visit the intensive care unit (ICU).
- Increased risk of infection. Some CAR-T therapies target a protein called CD 19, which is present on the surface of most B cells (another type of white blood cell). Like T cells, B cells help fight infection. However, CAR-T therapies that target the CD 19 protein also destroy B cells, making it difficult for a patient to fight infection. In this case, a patient can undergo immunoglobulin therapy.
- High uric acid levels in the blood (tumor lysis syndrome). Uric acid levels can increase when cancer cells break down quickly as it's difficult for the kidneys to cope with high levels of uric acid. Patients have regular blood tests to check for tumor lysis syndrome, and there are treatments available to reduce the levels of uric acid in the blood.
How Much Does CAR-T Therapy Cost?
Different companies manufacture different types of CAR-T therapies and at different costs. For example, while Kymriah's therapy costs $475,000 per patient, Yescarta's therapy costs $373,00. These costs will shift as more CAR-T therapies gain approval for wider patient populations.
How Will CAR-T Therapy Change?
CAR-T techniques have rapidly developed over the past year. That said, obtaining patient samples can be difficult, expensive, and time-consuming. As a result, there has been a widespread shift from autologous therapies to allogeneic therapies, which can be used "off the shelf". This transition is still in its early days.
Meanwhile, many manufacturers are under pressure to minimize manufacturing timescales, which means reducing the time dedicated to release testing. This testing contributes to the timescales required to manufacture and release CAR-T therapies for delivery to patients. Release testing can add as much as 100% to the time from apheresis to formulation. It is not yet clear how to reduce testing timescales.
Although many academic centers (as opposed to commercial entities) are sponsoring trials, we are also now seeing a shift to commercial production. Manufacturers will need to scale up production to meet demand. Then, new approvals will be granted, and we will see new patient populations. A roadmap for large-scale CAR-T production needs to recognize that quality control testing is an important part of this.
As new therapies gain market approval, technologies advance, and the regulatory framework adapts, the CAR-T space will continue to evolve. For example, combination therapies like the use of CART-s with checkpoint inhibitors could increase cost pressure on production. Meanwhile, new therapies that have different antigen targets (beyond CD19), use precisely selected T cell populations (beyond CD3+), and use different transduction methods could change the methods of quality control testing.
Manufacturers are now working with regulators to agree on quality control testing methods for individual therapies. Regulators are also making more efforts to provide detailed guidance on the release tests needed at each phase in clinical trials and commercial production. Meanwhile, technology developers are working to progress technologies that will standardize, increase the pace of, and lower the cost of CAR-T therapies in preparation for regulatory approval.
Visit RegMedNet to learn more about CAR-T therapy.
About RegMedNet
RegMedNet is one of Future Science Group's community websites. As a progressive scientific and medical publisher, Future Science Group fuels the development of clinical practice and drug research by providing platforms for communication among clinicians, researchers, and decision-makers. RegMedNet serves an ever-growing multidisciplinary community and provides critical overviews of treatment developments as these treatments evolve into mainstream medicines. RegMedNet's recent features on Car-T therapies include spotlights on allogeneic CAR-T therapies and CAR-T cell monitoring by droplet digital PCR.
Meanwhile, RegMedNet's sister journal Regenerative Medicine publishes some of the highest-quality papers and reviews in the fast-paced sector. This content spans the whole regenerative medicine field and highlights several approaches to regenerative medicine. These approaches include biologics, cell and gene therapies, small molecule drugs, and biomaterials and tissue engineering. The journal offers a specialist forum that addresses the industry's challenges and progression in regenerative medicine, publishing materials in clear, accessible article formats.
Together, RegMedNet and Regenerative Medicine enable users to watch, listen to, and read vast amounts of content that delve into regenerative medicine and the development, trialing, manufacture, regulation, and commercialization of cell therapy.
* This is a contributed article and this content does not necessarily represent the views of sciencetimes.com
