CLL is the most frequently diagnosed form of adult leukemia in the United States. About 15,000 cases a year are diagnosed, and 4,500 people die of it. Nearly 101,000 Americans are living with or are in remission from CLL.
CLL is called “chronic” because it is characterized by a long asymptomatic phase that can last many years without treatment. But the disease slowly progresses until it is symptomatic. At this point, chemotherapy is required, often producing a remission—which, unfortunately, is nearly always temporary. Almost all patients relapse.
The OSUCCC-James researchers discovered that CAL-101 obstructs the action of a molecule called PI3K-delta, which is found chiefly in blood-forming, or hematopoietic, cells, the very cells in which CLL arises. CLL cells contain a high degree of PI3K-delta and show strong activity in the PI3K pathway, a cellular series of chemical reactions. PI3K-delta and PI3K are closely related chemically.
Happily, the scientists found that CAL-101 kills CLL cells over normal B cells, a variety of white blood cells affected by CLL. Moreover, they discovered, CAL-101 does not kill other normal white blood cells called T cells and NK cells. Nor does it reduce antibody activity.
“Overall, our findings provide a rationale for the development of CAL-101 as the first in a new class of targeted therapies for CLL,” said principal investigator Amy J. Johnson, assistant professor of hematology and medicinal chemistry, and a CLL researcher in the OSUCCC-James.
“A PI3K inhibitor hasn’t been developed yet because this pathway is required for many essential cellular functions, but the identification of PI3K-delta, which is hematopoietic-selective, unlocks a potential new therapy for B-cell malignancies,” she said.