Anti-CD117 chimeric antigen receptor (CAR) T-cell therapy showed strong early potential to target and control advanced systemic mastocytosis (SM), according to preclinical findings published recently in Leukemia.
“Our study demonstrates as a proof-of-concept the effectivity of CAR T-cells directed against KIT D816V+ [mast cells] in preclinical models of [advanced SMAdvanced SM In these subtypes of SM, mast cells begin to damage organs. Advanced SM includes the subtypes aggressive SM, mast cell leukemia and SM with an associated hematological neoplasm.],” explained the study’s authors.
In SM, mutated mast cells grow uncontrollably and build up in organs such as the bone marrow, skin and liver. Researchers have been searching for new ways to directly eliminate these harmful cells.
In this study, scientists focused on CD117, a protein found at very high levels on mast cells. They engineered CAR T cells, a type of immune cell modified to recognize and attack specific targets, to seek out CD117.
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In laboratory experiments, these engineered cells destroyed mastocytosisMastocytosis Rare disease caused by the buildup of mast cells. Cutaneous mastocytosis primarily affects the skin and is more common in children, while systemic mastocytosis affects internal organs and is more common in adults.-related mast cells with high efficiency. At certain ratios, more than 90% of target cells were killed within days, and even at lower doses, meaningful cell death still occurred.
Importantly, the treatment worked regardless of whether the mast cells carried the common KIT D816V mutation, which is often linked to more aggressive disease. The CAR T cells also showed sustained activity over time, maintaining more than 95% control of mast cellMast cell A type of white blood cell produced in the bone marrow. They help defend against infections and play a key role in allergic reactions. In SM, mast cells become overactive and build up throughout the body. growth in long-term experiments. They became activated, multiplied and released signaling molecules that help drive an immune response.
The therapy was also tested on cells derived directly from patients, including bone marrow samples. In these cases, CAR T cells eliminated a majority of diseased cells, including about 70% of mast cells in patient samples after three days. This suggests the approach may work beyond artificial lab models.
In mice implanted with human mastocytosis cells, repeated doses of CAR T cells slowed disease progression and, in some cases, cleared detectable disease from blood, bone marrow and organs. While some signals suggested small amounts of disease might persist outside these areas, overall tumor burden was markedly reduced compared with untreated animals.
For patients with SM, these findings point to a possible future treatment that directly targets and removes disease-causing cells. However, the researchers cautioned that CD117 is also present on some healthy cells, including blood-forming stem cells, raising safety concerns that must be addressed in clinical trials.
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