"This duration and level of persistence of second-generation CAR T-cell has not been observed before," Dr. J. Joseph Melenhorst of the Perelman School of Medicine, University of Pennsylvania in Philadelphia, told Reuters Health by email.
"We demonstrate that individual CAR T-cells/CAR T-cell clones expanded, cleared the leukemia, and maintained activity for such a long time," he said. "This means that the memory function of immune cells, the very same principle at the heart of vaccinations against common and emerging viruses etc., apply to CAR T-cells also."
"We noted that while the initial anti-leukemia CAR T-cell population constituted predominantly killer cells with CD4-positive T cells trailing in the shadows, this latter population was in fact the one taking center stage late after infusion," he noted. "This long-term persisting population of CAR T-cells, the CD4-positive CAR T-cells, were true multitaskers: These cells were cancer killers, proliferated, and had signs of helper function. In addition, we identified signatures highlighting their memory role."
The two patients with CLL were enrolled in a phase 1 trial and achieved complete remission in 2010 after treatment with CD19-redirected CAR T-cells. As Dr. Melenhorst indicated, the CAR T-cells remained detectable more than 10 years after infusion, with sustained remission in both patients.
Also as noted, a highly activated CD4+ population emerged in both patients, dominating the CAR T-cell population at later time points. The transition was reflected in the stabilization of the clonal make-up of the CAR T-cells, in which a small number of clones were predominant.
Single-cell profiling showed that, along with ongoing functional activation and proliferation, these long-persisting CD4+ CAR T-cells also had cytotoxic characteristics.
Longitudinal profiling showed that during the initial response phase, a population of gamma delta CAR T-cells expanded in one patient, along with the CD8+ CAR T-cells.
Dr. Melenhorst added, "Something else we discovered was that the highly activated CD4-positive CAR T-cells expressed proteins we typically associate with dysfunction, or 'exhaustion,' which suggests that they were in a state of 'constrained activation.'"
"You can compare that to a car with a brake: Stepping on the gas pedal will put the vehicle in motion (analogous to CAR T-cells becoming activated) while the brake will put it back to halt (analogous to the negative regulation provided by the exhaustion-associated proteins)," he explained. "In other words, we think that the exhaustion-associated immune regulatory proteins contribute to sustained memory."
Dr. Ahmed Sawas, an oncologist at Columbia University Irving Medical Center in New York City commented on the study in an email to Reuters Health. "These findings support the ongoing enthusiasm for the mechanism of adaptive cell therapy in cancer treatment. To see the CAR T-cells persist for more than 10 years is a proof-of-concept of the place CAR-T has secured in the future of oncologic therapy."
However, he noted, "Cost and initial toxicity remain a major concern for the CAR-T therapies. The therapies need to be much more affordable if they are to be administered to a large proportion of the patients with cancer. Toxicity limits the number of patients with cancer that can receive the therapy and compromises the potential success for those who undergo it."
Dr. Ahmidav Deol of the Karmanos Cancer Institute in Detroit also commented by email, noting, "The findings are in CLL patients treated with CAR T-cells. This Is not an approved indication. It would be interesting to see if the long-term persistence is seen in approved indications of CAR T-cells in patients who have long-term disease control. The persistence may be different in different products based on the co-stimulatory domain."
SOURCE: https://go.nature.com/3BdYEce Nature, online February 2, 2022.
By Marilynn Larkin
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