Leukemia and lymphoma are cancers of the blood cells. These cancer cells are still recognized as “self” cells by the immune system, which then fails to eliminate them. However, CAR T-cell therapy is a treatment approach that modifies T cells, a type of immune system cell, so that they have the ability to recognize and kill cancer cells.
The CAR T-Cell Therapy Process
T cells are white blood cells that play a key role in our immune system by searching for and destroying foreign substances in the body called antigens. They are well-equipped to take on a cold virus, but cancer is a different story. Blood cancers like lymphoma and leukemia occur because normal blood cells mutate, or change, into cancer cells, which invade the immune system cells, including T cells. Since these cancer cells are mutated versions of a person’s own normal cells, the immune system does not identify them as foreign or perceive them as threats. However, a treatment approach called CAR T-cell therapy helps the immune system actually recognize these cancer cells as a threat and eliminate them.
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CAR T-cell therapy uses a multi-step process to modify a person’s T cells:
Evaluation is the first step in determining whether someone is eligible for CAR T-cell therapy. Patients need to meet with their care team to determine if CAR T-cell therapy is an appropriate option. Currently, CAR T-cell therapy is only FDA approved for use as a secondary option for cancer treatment. Patients aren’t eligible for this type of therapy unless they have had two recurrences or relapses, or have never gone into remission following standard care like chemotherapy, or other cancer treatments. Some CAR T-cell therapies also have age-based criteria.
Collection is the next step, once a person is deemed eligible. Blood is drawn from a person’s body, and the T cells are separated from the rest of the blood. This is usually achieved by a procedure called leukapheresis. The plasma and red cells are then returned to the body.
Manufacturing phase is when the collected T cells are shipped to a facility where scientists add a gene to the T cells that instructs the cells to develop an artificial receptor called a chimeric antigen receptor, or CAR. Chimeric means that a person, organ or tissue has cells not originally from itself, such as from a transplant. Chimeric antigen receptors allow T cells to recognize and bind to antigens on the surface of the cancer cells, hence the name CAR T-cell therapy.
Vectors are delivered into T cells with genetic instructions that allow a normal T cell to become a CAR T-cell. Vectors are often derived from viruses because they are capable of entering cells to deliver genetic material, such as a working gene. But don’t worry, all viral genes are removed and the vector is modified to only deliver therapeutic genes into cells.
Modified T cells are then grown in a lab setting until there are millions of them. The T cells are then frozen and sent to the care center where the person receiving the therapy is being treated. Patients require conditioning (or lymphodepleting) therapy before the infusion of CAR T-cells, which is chemotherapy that creates space for CAR T cells to expand and increase in numbers within the body. This increase in numbers of CAR T-cells within the body is important because it ensures there are enough CAR T-cells to take on the tumor cells.
Infusion phase involves injecting the modified CAR T-cells back into the person’s bloodstream, where they will travel to locations of tumor cells.
Recovery period follows the infusion process, for usually two to three months. During this time, people are evaluated for side effects and monitored for how their body is responding to the treatment. This recovery period can occur in the hospital or with frequent clinic visits, and patients may require supportive treatments, such as antibiotics or blood transfusions. Ideally the person will go into remission following the treatment. However, there is also the potential for an adverse event like cytokine release syndrome, which is described in-depth in the “Risks” section below. Even with a successful recovery, it is essential that the patient continue with long-term follow up appointments as needed. As months or years pass, there needs to be data showing that the therapy is effective and long lasting.
Pathway to Treatment
FDA-Approved Therapies
There are currently six FDA-approved CAR T-cell therapies with others being researched.
- Abecma is approved for adults with relapsed or refractory multiple myeloma after four or more prior lines (different types) of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
- Breyanzi is approved for adults with certain forms of relapsed or refractory large B-cell lymphoma including diffuse large B-cell lymphoma (DLBCL) arising from indolent lymphoma.
- Carvykti is approved for adults with relapsed or refractory multiple myeloma after four or more prior lines (different types) of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
- Kymriah is approved for people under 25 with certain forms of leukemia and adults with certain forms of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma arising from follicular lymphoma.
- Tecartus is approved for adults with relapsed or refractory mantle cell lymphoma.
- Yescarta is approved for adults with certain forms of relapsed or refractory B-cell lymphoma, including diffuse large B-cell lymphoma arising from follicular lymphoma.
These therapies are offered at a limited number of sites which are specialized academic medical centers. Although patients can reach out directly to a treatment center that offers the therapy, it’s important to inform their primary medical provider of the decision.
These therapies are covered by many health insurance options, including Medicare. Interested patients or their care providers should contact their health insurance provider prior to treatment to determine its coverage, as well as what to expect as far as out-of-pocket costs. Manufacturers of the gene therapies often offer patient support services to assist in navigating the process.
Access to Treatment
ASGCT advocates for the ability of all patients that qualify for CAR T-cell therapy to have access to it. Some challenges to patient access to these therapies have included policies on how to reimburse hospitals for providing these therapies for patients with Medicare.
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The Society advocates for full coverage of CAR T-cell therapies in all instances for which the Food and Drug Administration (FDA) has approved the therapy, and through adequate reimbursement of hospitals for patients under Medicare, so they are able to offer this therapy to patients with all types of insurance. If you want to get involved in supporting these policies to promote patient access to treatment, please contact Christina Mayer at cmayer@asgct.org.
Treatment Pipeline
Researchers are currently running clinical trials for other blood cancer conditions that CAR T-cell therapy may be able to help with. To search for active and recruiting CAR T-cell therapy clinical trials in the U.S., visit the ASGCT Clinical Trials Finder and use the ‘diagnosis’ filter for a specific disease or the ‘modality’ filter to search only CAR T-cell therapies. The Blood & Marrow Transplant Information Network also has a list of medical centers offering CAR T-cell therapy.
Risks
CAR T-cell therapy may cause a severe adverse event, such as cytokine release syndrome. During the therapy, immune system cells become stimulated and release chemical messengers called cytokines. Too many cytokines can result in fever, trouble breathing and can even be life-threatening. CAR T-cell therapy can also result in neurological problems including delirium, agitation, difficulty speaking, and seizures. With this in mind, people are carefully monitored during the recovery period following treatment. The FDA is also requiring that hospitals and clinics that dispense Kymriah or Yescarta are specially certified to recognize and manage cytokine release syndrome and neurological events. In the case of cytokine release syndrome, medical professionals can treat life-threatening organ toxicities by administering a treatment called anticytokine therapy to patients.
Benefits
As they were being tested in the clinical trial process before FDA approval, both Yescarta and Kymriah saw positive outcomes. Over 80 percent of people who received Yescarta in clinical trials saw either a complete or partial response. A complete response means that there were no signs of cancer, while a partial response means that there was a reduction in the overall extent of the cancer. For children and young adults who were treated with Kymriah in clinical trials, over 80 percent of them saw their cancer go into remission. Some of these responses can last long-term, while in some cases people may have their cancer return. Researchers will continue to collect data about the long-term success of these treatments.
Get Involved
One way you can get involved is to connect with a patient advocacy organization. They have great resources and are a way to seek support or advice from other families and patients that are affected by blood cancers. The diseases may be rare, but you're not alone.