The CAR T-cell therapy tisagenlecleucel, marketed as Kymriah, was recently approved by the FDA for adults with certain types of non-Hodgkin lymphoma. This is the second CAR T-cell therapy approved for lymphoma and the second FDA approval for this drug.
Tisagenlecleucel uses the body’s own T cells to fight cancer. T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor that reacts to the cancer, and transferred back to the person.
The T cells are engineered to target a protein called CD19 that is common on B cells. A chimeric T cell receptor (“CAR-T”) is expressed on the surface of the T cell.
Last year, the FDA approved another CAR T-cell therapy, axicabtagene ciloleucel, marketed as Yescarta, for the treatment of diffuse large B-cell lymphoma (DLBCL).
Tisagenlecleucel was the first CAR T-cell therapy to receive FDA approval. It was approved in 2017 for the treatment of children and young adults with leukemia.
The new approval of tisagenlecleucel is for lymphoma — specifically DLBCL, high-grade B-cell lymphoma, and DLBCL that arises from follicular lymphoma — that has come back or gotten worse after prior treatment.
“definitely fills an important niche. But its impact, at least to begin with, will be limited,”
because the treatment is completely personalized and available only at certain cancer centers, said Wyndham Wilson, M.D., Ph.D., head of the Lymphoma Therapeutics Section of NCI’s Center for Cancer Research.
Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL or DLBL) is a cancer of B cells, a type of white blood cell responsible for producing antibodies. It is the most common type of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the USA and the UK.
It occurs primarily in older individuals, with a median age of diagnosis at approximately 70 years of age, though it can also occur in children and young adults in rare cases. DLBCL is an aggressive tumor which can arise in virtually any part of the body, and the first sign of this illness is typically the observation of a rapidly growing mass, sometimes associated with B symptoms — fever, weight loss, and night sweats.
About 60% to 70% of people with diffuse large B-cell lymphoma have lasting responses to their initial therapy. For people whose DLBCL does not respond or comes back after initial treatment, the capacity for a cure with conventional therapy is “very, very limited,” Dr. Wilson explained.
Likewise, DLBCL that arises from follicular lymphoma can be hard to treat and the long-term prognosis for some of these patients is poor. Follicular lymphoma can sometimes transform into DLBCL after patients receive treatment for follicular lymphoma.
FDA’s new approval makes available another CAR T-cell therapy that
“is likely to cure some patients [with DLBCL] who wouldn’t be cured with other available strategies,”
Dr. Wilson said.
The JULIET Trial
The new approval was based on results from a phase 2 clinical trial called JULIET, for people with relapsed or refractory DLBCL who previously had at least two systemic cancer treatments or a stem cell transplant. Novartis, the manufacturer of tisagenlecleucel, sponsored the trial.
Study participants received chemotherapy to eliminate their existing immune cells before receiving a single infusion of tisagenlecleucel.
Of the trial participants who could be evaluated, half had a response. Overall, 18% had a partial response, meaning their tumors shrank but not completely, and about one third of participants had a complete response, meaning all signs of the cancer disappeared.
Complete responses lasted longer than partial responses.
Study participants need to be followed for a longer period to determine how long their responses last, Dr. Wilson noted.
In about one-quarter of the patients, tisagenlecleucel caused a severe inflammatory reaction known as cytokine release syndrome (CRS), a known side effect of CAR T-cell therapy. And 18% of patients had a neurological event, another common side effect of CAR T-cell therapy.
“These things can be managed, and we’re learning more about how to do that,” Dr. Wilson explained. “But that doesn’t mean they can’t be severe or life-threatening for some patients.”
In addition to the potential side effects, tisagenlecleucel is limited in several ways, Dr. Wilson pointed out. Not all people with DLBCL are eligible to receive the treatment or have access to one of the certified treatment centers.
And it provides lasting benefits to only a minority of patients.
The FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy, a drug safety program intended to help reduce the occurrence and severity of treatment side effects like CRS and neurological toxicity. Under the program, health care providers at facilities where tisagenlecleucel is offered must be specially trained to monitor and manage these side effects.