Increased Understanding of CLL Tumor Biology Unlocks Targeted CAR T-Cell Approaches

J. Joseph Melenhorst, PhD

Although nuances in chronic lymphocytic leukemia (CLL) tumor biology drive treatment challenges, identifying the differences in how this disease behaves in the lymph nodes vs the blood may generate increasingly effective CAR T-cell therapies for patients with this disease, according to Jan Joseph Melenhorst, PhD.

“We have uncovered several mechanisms that may help us generate the next generation of CAR T-cell therapies,” said Melenhorst, who is director of Cell Therapy and Immuno-Engineering and the vice chair of Immunotherapy and Precision Immuno-Oncology at Cleveland Clinic in Ohio, in an interview with OncLive^® during the 2023 International Workshop on CLL.

In the interview, Melenhorst, who is also a member of the Immune Oncology Program at Case Comprehensive Cancer Center, discussed the evolution of CAR T-cell therapy in CLL, how continued research to better understand disease biology may result in more targeted products, and the importance of tumor cell activation during the administration of this modality.

OncLive: How might cellular therapies be utilized to overcome T-cell dysfunction in CLL?

Melenhorst: This topic is my area of expertise. I’ve been working on CLL for the past 10-plus years and have made discoveries to help us inform next-generation cell therapies for this disease. One [advance] we [have] made in CLL has been [leveraging] gene-modified patient T cells using CARs, [or CAR T-cell therapies], which have been FDA approved now for several indications.

In CLL, the durable response rates [achieved with CAR T-cell products] are low. The [phase 1/2 TRANSCEND CLL 004] trial [NCT03331198] has shown that 18% of patients [with CLL or small lymphocytic lymphoma (n = 9; 95% CI, 9%-32%; P = .00006)] achieved a complete response [(CR) with lisocabtagene maraleucel (Breyanzi)]. In our studies, we discovered that a big portion of this response can be traced back to the T-cell health status. [That is] an action item or biomarker we discovered. What we have also learned is that response rates [with CAR T-cell therapy] in CLL are largely predictable. By analyzing T cells, we also learned that CLL itself has an anti–immune-refractory function by simply not stimulating enough CAR T cells.

What is the importance of understanding T-cell function in CLL?

[The feasibility of] conducting an immunotherapy trial [in CLL] typically depends much on the function of the [patients’] immune systems [when they receive treatments] such as CAR T-cell therapies. Also, in recent data with bispecific antibodies, we’ve seen that the biology of T cells plays a big role in response rates. Regarding T-cell biology, the question I asked initially, over a decade ago, was: Why [do patients only] have an approximate 25% CR rate, [and why do] most patients not respond at all or respond only transiently? Because [CAR T-cell therapy] uses patients’ own immune cells, their T cells, the low-hanging fruit was to first interrogate these T cells’ function, and that investigation led to [several] discoveries.

How have you seen the CLL treatment paradigm shift over time?

CAR T-cell therapy [research] started in 2010, with [efforts by] James N. Kochenderfer, MD, of the National Cancer Institute [in Bethesda, Maryland], Carl H. June, MD, of the Hospital of the University of Pennsylvania [in Philadelphia], and Michel Sadelain, MD, PhD, [of Memorial Sloan Kettering Cancer Center in New York, New York]. The CAR design itself was optimized, meaning that the second-generation CAR was developed, [and that] proved to be the one with the best formulation. What we saw next was that [treatment] resistance is a challenge in CLL. Trials were run by the University of Pennsylvania using ibrutinib [Imbruvica] before T-cell collection and [other efforts are] using combination therapies and CAR T-cell therapies. That’s been the next phase of [research].

Other combinations will help us get high response rates with CAR T cells and small molecules. We’ve [also learned about] the CLL tumor itself. Adrian Wiestner, MD, PhD, [of the National Institute of Health in Bethesda], and many others are experts on CLL biology, and they study the tumors [that patients have if they] develop CLL, which mostly resides in lymph nodes.

We have collaborated over the years on understanding how CAR T cells respond differently to CLL cells in the tumor bed, which are biologically different from the CLL cells in circulation. We noticed that responses [to CAR T-cell therapy] in the lymph nodes were more profound with circulating resting CLL cells. Understanding the biology, integrating that into next-generation therapies, and [using] combination therapies enhances [CAR T-cell therapy] efficacy.

What factors are critical to consider when selecting or designing the target antigen for CAR T-cell therapy for CLL?

The antigen is exclusively expressed by either the tumor alone or the lineage it belongs to, such as CD19 on B-cell malignancies, including CLL. In CLL, we have an opportunity to make therapies even more selective. Some proteins are selectively expressed by CLL, such as ROR1. That [information] will probably [inspire] one of the new [treatment] developments. Lyell Immunopharma is working on making therapy more focused on tumor cells.

Based on findings from prior research, what does the future look like for CAR T-cell therapy research in CLL?

Part of the research my group published, [the findings from which were] a bit of a surprise to me, [showed that] when we used tisagenlecleucel [Kymriah] in CLL, even when taking the best possible, healthy T cells [for manufacturing,] they would not respond to CLL cells in circulation. We uncovered in our in vitro studies that, importantly, the additional hurdle is that the tumor cell itself has to be an active participant in its own demise. We found that if you briefly activate CLL cells, these CAR T cells are highly effective.

Studies on the biology [of CLL are] important, [as are] combination therapies that have an enhancing effect. One of the big challenges in CLL, too, is that when you conduct apheresis, the bulk of the cells [collected] are not T cells. Preselecting T cells prior to [CAR T-cell therapy] manufacturing is one step in the right direction, as are potential combination therapies.