A new weapon in the cancer immunotherapy revolution was launched in 2017 with the approval of two novel drugs based on CAR T-cell technology.
The first two U.S. Food and Drug Administration-approved CAR T drugs, known as tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), have achieved dramatic responses in some patients with advanced blood cancers who had relapsed after standard treatment. The drugs were initially approved only for certain patients as third-line treatment of B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma, or LBCL.
What are CAR T cells?
CAR T cells are made by removing some of the patient’s own immune cells and equipping them with an individualized laboratory-made receptor. When given back to the patient, these engineered cells act like a “living drug” — a one-time infusion of tailored T cells that home in on a specific protein on the patient’s cancer cells and mount an attack on the cancer.
While the treatments can have severe side effects, the availability of CAR T-cell treatments for some patients who otherwise had few options has been “totally transformative” and enables physicians to give a “message of hope,” says Caron Jacobson, MD, medical director of the Immune Effector Cell Therapy Program at Dana-Farber/Brigham and Women’s Cancer Center.
At present, the field is only in “the first leg of the CAR T journey,” as one assessment put it, with intense research underway to make the technology more widely applicable and safer.
Expanding CAR T-cell therapy to other cancers
Scientists believe there’s great promise for CAR T-cell therapy in blood cancers other than B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma, and possibly may be made effective against solid tumors as well. Several clinical studies are showing promise, Jacobson says.
One clinical trial is testing a modified CAR T cell product in patients with relapsed mantle cell lymphoma, a “huge unmet need,” she says. The drug, known as KTEX19, achieved a high response rate that was maintained in 65 to 75 percent of patients for a year. Another clinical trial is measuring the effectiveness of CAR T-cell therapy for lymphoma subtypes called marginal zone lymphoma and follicular lymphoma.
“Many people are hopeful that these therapies could change the course of the natural history of the disease,” Jacobson says.
Thus far CAR T cells have been reserved for patients with relapsed aggressive B-cell non-Hodgkin lymphoma who have gotten worse after two rounds of chemotherapy have failed. However, at least one study is now testing CAR T cells in patients with these lymphomas who have relapsed following one chemotherapy regimen and are unlikely to respond to further chemotherapy, says Jacobson.
“We are awaiting the data for relapse-free survival, and if this is positive, we may be able to move CAR cells from third-line to second-line,” Jacobson says.
Efforts are also under way to create and test CAR T cells to treat other blood cancers, such as Hodgkin lymphoma and acute myeloid leukemia (AML).
CAR T cells that take aim at multiple targets
Initially, CAR T cells were engineered to recognize just one distinctive antigen on the surface of cancer cells, such as the CD19 antigen in B-cell ALL. However, cancer cells can evolve to escape the immune attack by losing the primary target, making them invisible to the CAR T cells. Scientists are now devising CAR T cells that target multiple antigens in hopes of defeating this antigenic escape strategy.
Addressing side effects
Researchers are also working hard to understand, predict, prevent, and treat the toxic side effects that can be triggered after CAR T cells are infused into patients. Chief among them is cytokine release syndrome (CRS), a systemic inflammatory response that can be mild or severe and cause a number of complications such as fever, fatigue, low blood pressure, rapid heartbeat and pain.
A CAR T product in clinical trials, called lisocabtagene maraleucel, appears to have a lower risk of causing cytokine release syndrome, according to Jacobson. In one study reported in 2019, patients who received this product developed the syndrome later, if they did at all, and were less likely to have a severe form of it, so that many individuals could be monitored as outpatients rather than having to stay in the hospital.
‘Off-the-shelf’ CAR T cell products
A lot of research is underway to overcome a major limitation of current CAR T cell therapy: using the patient’s own immune cells to create the modified T cells.
For one thing, the patient’s immune cells may not be the most potent, due to the cancer and its prior treatments, and for another, it takes two to four weeks to process the cells before they can be given back to the patient. As a result, scientists are working toward “off-the-shelf” CAR T cell products — made from the immune cells of a healthy donor, frozen and stored. These CAR T cells could be given almost immediately when a patient needed them, says Jacobson. One healthy donor’s cells could also potentially be used to make CAR T cells for as many as 100 patients.