Chronic Lymphocytic Leukemia
Engineered Cellular Immunotherapy for Chronic Lymphocytic Leukemia
Chimeric antigen receptor (CAR) T-cell therapy is a promising technology, but studies have not led to a US Food and Drug Administration–approved product for chronic lymphocytic leukemia (CLL). Richter’s transformation (RT) is a rare but devastating complication of CLL for which CAR T-cell therapy has shown substantial promise.
The Gordon and Helen Hughes Taylor Professor and Chair
“ . . . RT of CLL is where I see CAR T cells potentially making a big impact, and this is a space in which nothing else that has been tried in the past has really worked.”
While CAR T-cell therapy is an approved option for mantle cell lymphoma and large B-cell lymphoma, data showing the benefits of this approach in CLL have been more limited. There are some reports of patients with CLL surviving more than 10 years after receiving an infusion of CD19-specific CAR T cells; however, most studies have found that fewer than 50% of patients with CLL achieve complete remissions. Most recently, the primary analysis of the single-arm phase 1/2 TRANSCEND CLL 004 study reported a complete response rate of only 18% with the administration of the CD19-targeted CAR T-cell product lisocabtagene maraleucel. This was in a population that was characterized by treatment failure with a previous Bruton tyrosine kinase (BTK) inhibitor, with a large subset also having experienced venetoclax failure.
I think that part of the problem relates to the compromised T-cell function and the unfavorable microenvironment in patients with CLL from whom T cells are collected for CAR T-cell manufacturing. Our group, together with the group led by Carl H. June, MD, at the University of Pennsylvania, have produced data suggesting that BTK inhibition may help with T-cell function in that regard.
So, as the field moves forward, having an effective cellular therapy will certainly be important, but we also need to address the immunosuppressive microenvironment in CLL. This is something to watch for on the horizon, along with the development of other promising engineered cell therapies for CLL, such as CAR-engineered natural killer cell therapies and bispecific T-cell therapy. For now, until we can show that CAR T-cell therapies are inducing real, durable remissions that are potentially curative or that are enabling patients to have incredibly extended treatment-free periods, the potential advantages, in my view, are marginal when we have other options with less toxicity.
In contrast, RT of CLL is where I see CAR T cells potentially making a big impact, and this is a space in which nothing else that has been tried in the past has really worked. RT is not a common complication of CLL, but it is devastating when it happens. When we see a diagnosis of RT, our current approach is to treat as effectively and expeditiously as possible on the way to a CAR T-cell trial or protocol, and many groups are now also taking this approach. The data are still limited in terms of the overall numbers of patients, but it does not take too many patients to know when something is making a big difference for an extended period of time.
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