With No CAR-T Cell Therapies Approved for CLL, More Work is Needed to ‘Maximize’ These Treatments

Some of the earliest trials of CAR-T cell therapy have been in patients with chronic lymphocytic leukemia (CLL), though the space still lacks a Food and Drug Administration (FDA)-approved CAR-T cell treatment.

“CLL was among the first diseases treated with CAR-T cells and certainly among whom the first we saw successful (data), but we still don’t have any approved products,” said Dr. John G. Gribben, Hamilton Fairley professor of Medical Oncology at the Barts Cancer Institute in London, at the recent EHA-EMBT 4th European CAR T-Cell Meeting.

CAR-T cell therapy works by extracting a patient’s blood, engineering the T cells to better find and fight cancer and then infusing that blood back into the individual. Gribben explained in his presentation that patients with CLL may be starting at a disadvantage from the get-go.

“T cells that we obtain from these patients are going to be impaired in their function as the starting material for making the CAR-T products,” he said, noting that T cells drawn from patients with CLL often exhibit signs of “pseudo-exhaustion,” which makes them less aggressive cancer killers. “We do believe that the fact that there are these intrinsic T cell defects in some way explains why we’re seeing perhaps less good responses in this disease setting historically than we’ve seen in diffuse large B cell lymphoma, acute lymphoblastic leukemia and myeloma.”

But there may be ways to improve the function of these less-than-ideal T cells. For example, Gribben cited research being conducted at the University of Pennsylvania and the Fred Hutchinson Cancer Research Center in Seattle that showed that giving patients Imbruvica (ibrutinib) before undergoing CAR-T cell therapy may improve outcomes.

“When we look at these kinds of studies, we are seeing better progression-free survival than we saw in some of the early, phase 1 studies, but (there is) still room to improve. We are seeing both durable responses as well as the ability of the CAR-T cells to induce eradication of residual disease,” Gribben said.

There are also alternatives to CAR-T cell therapy that are being explored, too.

Gribben mentioned the use of CD19 CAR-natural killer (NK) cells. These products are “off the shelf,” meaning that they do not need to be created by and formulated for one specific person. This may be a work-around to the pseudo-exhaustion seen in the T cells of many patients with CLL.

NK cells are a type of immune cells found in the human body that fight tumor and virus-infected cells.

Additionally, Gribben said that cord blood-derived NK cells are also promising, and studies have shown that they tend to lead to lower rates of graft-versus-host disease (GVHD). But still, there is more research that needs to be conducted.

“There’s still more work to do in terms of really maximizing the capacity of these NK CAR-T cells to engender durable responses in more CLL patients,” Gribben said.

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