In some patients with lymphoma, their own immune cells engineered with an added receptor persisted for up to ten years
In some patients with lymphoma, their own immune cells engineered with an added receptor persisted for up to ten years
On August 10, a Nature Medicine paper described 38 patients with B-cell non-Hodgkin lymphomas who received a single infusion of these cells. Samples collected after year five were available from eight patients with long remissions. In five of them, the added receptor gene remained detectable 7.0–10.1 years after treatment.
CAR-T cells are made from a patient’s T-cells, which are immune cells engineered in the laboratory to express an artificial receptor. In this study, the receptor recognized CD19, a protein found on B-cell lymphoma cells and on normal antibody-producing B-cells. The therapy can therefore attack the tumor while also depriving the patient of part of their protection against infection for an extended period.
In 2014, the University of Pennsylvania began a trial of this therapy in people with B-cell lymphomas that had returned after treatment or had not responded to it. The long remissions left an unresolved question: did the infused cells disappear after the initial attack, or did they continue to circulate and recognize CD19? The authors of the new paper returned to later samples from the same cohort.
After year five, 12 patients remained in remission, but suitable samples were available from only eight. The CAR gene was detected in the DNA of five patients. B-cells were still absent in all three patients with more than 200 copies of the gene per microgram of DNA, whereas B-cells had recovered in the two patients with weaker signals. A strong CAR signal therefore coincided with a continuing effect on B-cells.
The most detailed analysis concerned a 68-year-old patient with follicular lymphoma. After 9.3 years, CAR-T cells accounted for 1.2% of all T-cells in her blood, and her remission lasted 10.1 years. Almost 70% of the late CAR-T cells descended from a single T-cell. On day 14 after the infusion, this clone had represented less than 0.1% of the population. The cells continued to divide and retained features associated with the ability to kill target cells.
In the same patient, the prolonged absence of B-cells caused a severe antibody deficiency. She received monthly immunoglobulin infusions, which provide ready-made antibodies. Recurrent infections and bronchiolitis began in the ninth year. The authors discuss two ways to reduce this cost: selectively removing CAR-T cells in patients with severe or recurrent infections, or designing receptors that recognize malignant B-cells while sparing normal ones.
When CAR-T cells persist for years, clinicians need a way to switch them off temporarily during severe infections. In a cell experiment, caffeine temporarily suppressed CD19 CAR-T signaling. A switch of this kind could limit the effect on normal B-cells.