Long-Term CAR-T Results in Lymphoma Confirm Early Promise

Ten years after receiving a single dose of CD19-targeted CAR T-cell therapy, almost a third of patients with aggressive lymphomas and no treatment options remained lymphoma free, updated results from a landmark trial showed.

Overall, 12 of 38 patients remained lymphoma-free at 10 years, half with heavily pretreated large B-cell lymphoma (LBCL) and half with relapsed/refractory follicular lymphoma. No relapses occurred after 5.4 years of follow-up, and no patient with follicular lymphoma relapsed after 2.7 years. The 10-year overall survival was 17% among 24 patients with LBCL and 50% for the 14 with follicular lymphoma.

The results show that CD19-directed CAR T-cell therapy not only can achieve long-term remissions but may possibly cure some patients, reported Marco Ruella, MD, of Penn Medicine in Philadelphia, and colleagues in the New England Journal of Medicine.

The results exceeded even the most optimistic expectations at the start of the trial.

“I thought none of [the patients] would be alive at 5 years, and it turned out that most of them were,” co-author Stephen Schuster, MD, also of Penn Medicine, told MedPage Today. “Once I saw the 5-year data, I thought ‘Oh my god, maybe — I hate to say cure — but maybe we’ve cured patients.’ We addressed that question by saying, well, if you live as long as an age- and gender-matched American and you die of unrelated causes and your lymphoma is in complete remission, then that’s essentially a cure. Sure enough, our patients matched what you would kind of expect, so I think we can safely say we’re curing some patients, and I think we’ll cure more in the future.”

Another CAR T-cell researcher had high hopes early on, especially after seeing data from single-center studies conducted at the University of Pennsylvania and elsewhere.

“We were super excited and hopeful that [CAR T-cell therapy] would lead to long-term remissions, or at least high remission rates for patients without other options,” said Frederick Locke, MD, of Moffitt Cancer Center in Tampa, Florida, who helped organize and coordinate multicenter trials. “The durability was unclear. This study is just now at 10 years and we treated our first patient in 2015, so about 10 years ago. We were hopeful, and we couldn’t have been more pleased with the results we saw. Now the therapies are FDA approved and more widely available, although we need to do more work to make them even more available.”

Study Background

The Philadelphia study involved the CAR construct known as CTL019, subsequently named tisagenlecleucel (Kymriah). Investigators enrolled 49 patients from January 2014 to September 2019, and data cutoff occurred Oct. 1, 2025. Eleven patients did not receive the CAR T-cell therapy, five because of rapid disease progression, five because the manufacturing yield was inadequate for the specified dose, and one patient withdrew consent.

The overall 10-year lymphoma-free survival was 38% (defined as the time from CAR T-cell infusion to relapse or death), including 32% in the patients with LBCL and 47% for those with follicular lymphoma. Most treatment failures or relapses occurred within the first year after infusion, consistent with previous reports. An analysis that included deaths from any cause showed a 10-year progression-free survival of 17% in the patients with LBCL and 29% in the follicular lymphoma group. The 10-year incidence of non-relapse-related death was 18%, decreasing to 14% with exclusion of deaths related to COVID.

With respect to safety, two patients had persistent grade 2 or 3 neutropenia. No patients developed late anemia or thrombocytopenia. Nine patients developed second primary cancers, consisting of three cases of treatment-related acute myeloid leukemia, two cases each of prostate cancer and non-small cell lung cancer (both involving smokers), and one each of mycosis fungoides and melanoma. The 10-year cumulative incidence of second primary cancer was 21%, as compared with a 10-year cancer risk of 11% for a matched population from the Surveillance, Epidemiology, and End Results database.

Best Yet to Come

Schuster has high expectations for continued improvement in outcomes with CAR T-cell therapy. Development of more effective therapies for lymphoma, such as bispecific antibodies, is one factor contributing to the optimism.

“We’ve learned that the most important factor for successful outcome, particularly in large B-cell lymphoma, is disease control prior to CAR T-cell therapy,” said Schuster. “Patients [whose disease] is actively growing are the ones more likely to fail. Those who have at least stable disease or partially responding disease to any kind of therapy prior to CAR T cells are likely to have a better response.”

Increasingly sophisticated assays for circulating tumor DNA will help determine the extent and depth of response to preceding therapies to guide decisions about continuing to CAR T-cell therapy. Recent studies have shown that the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica), given before and after CAR T-cell infusion, enhances T-cell activation toward more cytotoxic T cells, which could make CAR T-cell therapy more effective.

Ongoing studies to develop rapid culturing techniques offer the potential to speed up the CAR T-cell production process and also produce more effective and durable therapy, said Schuster. The next generation of studies will use less differentiated T cells that are capable of serial cancer cell killing and then regenerating themselves. A shortened processing time would be especially beneficial for patients with aggressive B-cell lymphomas. A recent study showed that only 25% of patients potentially eligible for CAR T-cell therapy actually received the treatment, owing to access issues, production issues, and patient-related characteristics.

Further on the horizon, off-the-shelf allogeneic CAR T-cell products appear to be a viable alternative to autologous cells. Preliminary studies suggest results could rival those of conventional autologous products.

“That totally gets away from manufacturing, and that would also include patients that would fail manufacturing because they have bad lymphocyte counts,” said Schuster.

Also further out, so-called in vivo CAR T-cell therapy offers potential to get around obstacles posed by the production process, said Locke.

“The CAR T cells are made within the patient’s own body, instead of taking the T cells out and delivering the vector to the CAR T cells and expanding them in a laboratory and then reinfusing them into the patient,” he said.

Another evolving technology that could eliminate some of the production and processing obstacles involves lipid nanoparticles that deliver the “CAR machinery” to T cells.

“We’ve seen some pretty incredible clinical results in China and Australia,” said Locke. “We need to get those therapies to the United States and tested more rapidly. The regulatory and other hurdles are different in China and Australia. We’d like for the U.S. to be the first place to test these therapies. But we’re still excited for our patients that we’re seeing great results.”

Said Schuster, “All these things are converging, I believe, to give us a future that will show us much better results than these results that are now 10 years old.”

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