Since the Food and Drug Administration (FDA) designated it a breakthrough therapy in 2014, this cellular therapy has become more widely available. And researchers have continued to push ahead to make CAR T cell therapy even more effective with fewer side effects while making it an option for more patients.
Fitter T cells may mean more effective CAR T cell therapy
There are now several CAR T cell therapies commercially available, but they’re only approved for use as a second-line therapy and beyond. That means it is only an option for cases where the cancer either didn’t respond or returned after the patient received an attempt at standard therapy, which is typically chemotherapy.
With each round of treatment, the quality of the T cells declines. “The cells are beat up; they’re not as functional,” Neelapu says. And since CAR T cell therapy is created from the patient’s own T cells, the fitness of the T cells becomes a challenge.
But moving CAR T cell therapy to earlier lines of therapy would mean better quality T cells and perhaps more effective CAR T cell therapy.
Led by Neelapu, the ZUMA-12 clinical trial is exploring the CAR T cell therapy axicabtagene ciloleucel, often called axi-cel for short, as a first-line therapy. Patients newly diagnosed with large B-cell lymphoma receive at least two rounds of standard chemotherapy. If they haven’t achieved complete remission, they receive CAR T cell therapy.
The ZUMA 1 clinical trial, which led to the first approval of a CAR T cell therapy, also evaluated axi-cel in patients with large B-cell lymphoma but as a third-line therapy.
When comparing the T cells of patients in the ZUMA-12 to those of patients in the ZUMA-1 trial, the T cells appeared better. “They’re younger, fitter cells,” Neelapu says. The fitter T cells also expand more than the older cells, he adds, so they build a larger offense against the cancer. Data from ZUMA-12 indicates that patients who receive axi-cel as their initial therapy have much higher complete remissions rates than those who receive it as a third-line therapy. Neelapu says there is a similar ongoing clinical trial in pediatric patients with acute lymphoblastic leukemia.
Two clinical trials have been completed looking at CAR T cell therapy as second-line therapy in patients with large B-cell lymphoma. Data shows the CAR T cell therapy was more effective when compared with an autologous stem cell transplant, which is the standard of care for when the cancer relapses after a patient receives a combination of chemotherapy and immunotherapy. Because of these findings, axi-cel and lisocabtagene maraleucel are approved as a second treatment course for patients with large B-cell lymphoma.
“So far, the data indicates that CAR T is probably a better treatment than existing therapies, both in the second- and third-line settings, and early data suggests that may be the case in first-line as well,” Neelapu says.
Fitter T cells don’t equate to more severe side effects
Although fitter T cells seem to translate into a more effective product, Neelapu says that it doesn’t necessarily equate to more severe side effects. That’s because the severity of the side effects depends not only on the degree of expansion of the T cells, but also the amount of cancer in the body.
“We may not be seeing increased side effects, in part, because patients who receive the product in the second and frontline settings have less cancer in their body,” Neelapu says.
CAR T cell therapy helps patients return to normal life sooner
Chemotherapy for lymphoma often lasts around six months. For leukemia patients, it can take longer than a year. However, CAR T cell therapy is a single infusion.
Side effects of chemotherapy can take months to subside or linger for years, but most of the CAR T cell therapy side effects appear within the first two weeks after the infusion. All in all, CAR T cell treatment can be done in as little as month, Neelapu says. “A patient can get back to their usual activities sooner, so that’s a huge benefit,” he says.
Engineering donors’ T cells could benefit patients
One of the challenges with moving CAR T cell therapy to earlier lines is the logistics of testing the therapy in a large patient group through a Phase III randomized clinical trial. Because CAR T cell therapy is a patient-specific product, the therapy would need to be manufactured for each patient.
But another area of CAR T cell therapy research is exploring using T cells from healthy donors to create the cellular therapy. Although it’s still early in this area of study, Neelapu says an allogeneic CAR T cell therapy would mean an off-the-shelf option that would benefit patients in several ways.
First, it could improve access. Neelapu says less than 20% of eligible patients are receiving the CAR T cell therapy. “There are only about 100 CAR T centers in the U.S., which averages to about two per state,” he says. “It’s probably not enough.” Many patients and their caregivers must relocate to a CAR T cell center for five to six weeks to receive the therapy. “With an off-the-shelf product, an apheresis center wouldn’t be needed – only a freezer to store the product, and trained personnel to administer the therapy intravenously. The therapy could be offered at more locations, making it accessible to more patients.
Second, as an off-the-shelf therapy, patients won’t have to wait the five to six weeks it takes to create the personalized product. “Some patients can’t wait that long,” Neelapu says. He hopes that by having the therapy available immediately, more patients can receive it and benefit.
Lastly, an off-the-shelf option can help reduce manufacturing failures. For example, when a patient’s T cell numbers aren’t high or the cells aren’t functioning well when harvested, they don’t make the release criteria to be made into the therapy. “With a healthy donor, we could make at least 100 doses and sometimes more,” Neelapu says. Preclinical studies are also showing that donated cells are fitter and have better function.
Overcoming treatment resistance with new targets
Researchers are also focused on identifying new targets to help overcome treatment resistance in patients who don’t experience long-term remission with CAR T cell therapy. Unfortunately, about a third of patients who relapse after CAR T cell therapy experience antigen loss. This means the tumor cells aren’t expressing the current target of CAR T cell therapy, CD19.
To address antigen loss, Neelapu is researching a new target for CAR T cell therapy called CD79b, which is expressed on both leukemia and lymphoma cells.
“The long-term goal is to actually target both CD19 and CD79b together at the same time with a bispecific CAR T cell,” he says. “I think that we’ll see improvement in the efficacy and see more patients enjoy longer remissions.”