Chimeric antigen receptor T cells remained detectable in two early recipients who sustained decade-long remissions. The cells’ characteristics had shifted over the years, however, with CD4-expressing cells that retained anticancer activity becoming dominant.

Oncologists don't use the word “cure” lightly. But in February, Carl June, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, declared: “We now conclude that CAR T cells can actually cure patients with leukemia.”

June came to that conclusion after analyzing blood samples from two men who were among the earliest beneficiaries of adoptive T-cell therapy. In 2010, both patients received CD19-redirected chimeric antigen receptor (CAR) T cells as a treatment for refractory chronic lymphocytic leukemia (CLL).

More than a decade later, neither man showed any sign of cancer—one remains alive and still in remission; the other died of COVID-19 complications last year. And circulating within each patient's blood were leukemia-fighting engineered T cells that still bore the CAR constructs added years earlier (Nature 2022;602:503–9).

The characteristics of those designer immune cells had shifted, however.

Within a few months of infusion, the CAR T cells were mostly of the CD8+ “killer” variety that helped eradicate leukemic cells. Cell profiling also revealed a smaller population of gamma-delta CAR T cells, so-named because they express γδ T-cell receptors but neither CD4 nor CD8. These cells likely played an anticancer role in the early days of treatment as well, the authors concluded.

Over the years, however, those populations gave way to CD4-expressing cells, which came to dominate the CAR T-cell pool. In the lab, these long-lasting CD4+ CAR T cells showed signs of functional activity and proliferative capacity. Plus, they retained the ability to destroy CD19-expressing cells.

These findings suggest that CD4+ CAR T cells are “uniquely poised to stay on surveillance for a decade,” June said—although, without any lingering leukemia in either patient, researchers don't know whether or how the cells contribute to maintaining remission.

“It still begs the question of how long they need to persist,” said Jae Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY, who was not involved in the research.

Park and his colleagues have also found that CD19-targeted CAR T-cell therapies can yield persistent and durable remissions, albeit in patients with acute lymphocytic leukemia rather than CLL (N Engl J Med 2018;378:449–59). Yet, in those cases, the CAR T cells did not stick around. Some patients remain leukemia-free to this day, even without these immune cells in circulation.

One explanation for the difference in persistence could be the co-receptor signaling domain included in each group's CAR construct: June and his study co-leaders, J. Joseph Melenhorst, PhD, and Kai Tan, PhD, used CD28, whereas the MSKCC researchers used 4-1BB. (Both domain types are found in approved CAR T-cell products on the market today.)

So, while the findings from June and his colleagues “provide very strong evidence that persistent CAR T cells are possible,” Park said, it's unclear whether that kind of cellular response is needed for patients to gain the full benefits of engineered T-cell therapies. “It is hard to generalize to all CARs.” –Elie Dolgin

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©2022 American Association for Cancer Research.
2022
American Association for Cancer Research.