CAR T-Cell Therapy Makes its Mark in CLL

David L. Porter, MD

Patients with chronic lymphocytic leukemia (CLL) have already benefitted immensely from the development and clinical application of CAR T-cell therapies, and investigators are aiming to fill remaining unmet needs by refining optimal administration practices, according to David L. Porter, MD.

“Patients with CLL were some of the very first patients we treated [with CAR T-cell therapy] here at the University of Pennsylvania back in 2010,” Porter said. “So, we have a long experience [with these agents]; we have follow-up now of over 13 years in some of our initial patients who were treated.”

In March 2024, lisocabtagene maraleucel (liso-cel; Breyanzi) became the first CAR T-cell therapy to be approved by the FDA for the treatment of patients with CLL or small lymphocytic lymphoma, gaining approval in patients who received at least 2 prior lines of treatment, including a BTK inhibitor and a BCL-2 inhibitor. The approval was supported by findings from the phase 1/2 TRANSCEND CLL 004 study (NCT03331198) which showed patients treated with liso-cel (n = 65) achieved a complete response (CR) rate of 20% (95% CI, 11.1%-31.8%). Notably, the median duration of response (DOR) was not reached (NR; 95% CI, 15 months-NR) at the data cutoff; the 12- and 18-month DOR rates were 100% and 87.5% (95% CI, 38.7%-98.1%), respectively.

In an interview with OncLive®, Porter, the director of the Center for Cell Therapy and Transplant, as well as the Jodi Fisher Horowitz Professor in Leukemia Care Excellence at Penn Medicine in Philadelphia, Pennsylvania, discussed the highlights from a presentation he gave during the 2024 Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium in May regarding the current standing of CAR T-cell therapy in the CLL treatment paradigm as well as the unmet needs and future research avenues in the space.

OncLive: What were some of the key data you presented that support the use of CAR T-cell therapies in CLL?

Porter: There have been a lot of data [on] using CAR T cells to treat [patients with] relapsed/refractory CLL. Some of the most important data are the poor outcomes that you see with these patients who receive conventional therapies. CAR T cells have the potential to be transformative.

There are data from clinical trials [with CAR T-cell therapy] showing a significant response rate in these patients, with a CR rate of approximately 30% to 60%. But I believe the most important data [are those that show] that although [this therapy] doesn’t work for everybody, when it works, it works extremely well. Many of the patients who achieve a CR have long-term CRs. That’s critically important, particularly in a group of patients who otherwise have very few treatment options. Indeed, the accumulated data suggest that many of these patients who have achieved CR and who are ongoing [in response] for a number of years have likely been cured of their disease.

There are some other data [which are] a little bit newer and experimental combining CAR T cells with BTK inhibitors, such as ibrutinib [Imbruvica]. [My group] and others have presented clinical trial data for patients who have been on ibrutinib who then receive CAR T cells and they suggest that response rates are significantly higher. There’s a very high probability of achieving minimal residual disease [(MRD) with that approach]. Although the outcomes of using CAR T cells for patients with relapsed/refractory CLL are quite impressive, the outcomes may be even better in the future when combined with some newer therapies.

Are there certain institutional processes that can streamline the delivery of therapeutics such as CAR T-cell therapy?

There are important institutional processes that have made this logistically more practical. We have a very robust program here at Penn in delivering CAR T-cell therapy in an outpatient setting. It requires some institutional logistics, setup, and resources to be able to do that and manage these patients. This has been done in other sites as well.

I can say we have treated most of our patients with CLL who get CAR T cells in an outpatient setting; that is good patient care. Patients much prefer to be at home than having to be in the hospital for 1 or 2 weeks. If it’s set up, it can be done quite safely, [and] it’s cost effective. It makes the whole episode of care much more practical and acceptable to patients, and to caregivers who prefer to treat their patients in an outpatient setting as well.

What are some of the data gaps that remain in this space?

We know that when CAR T-cell therapies work for patients with relapsed/refractory CLL, the responses can be quite dramatic. We have patients now who were treated almost 14 years ago who remain in remission. One of the biggest limitations of CAR T is that, when it works it works extremely well, but it doesn’t work often enough. Even the clinical trial data that led to the recent approval of liso-cel for relapsed/refractory CLL were quite impressive in a group of patients where no other treatment is effective, yet only [showed] a CR rate of approximately 18%. One of the biggest gaps is trying to improve the CR rates for more patients.

That may be [done] with combination therapies, including administering CAR T cells with therapies such as ibrutinib or other BTK inhibitors. The addition of ibrutinib to regimens, or prior treatment with ibrutinib, may increase response rates and potentially even durability of response. We need to have good long-term follow up of these patients. CLL is a chronic disease, and late relapses are possible, though many of these patients have far advanced, multiply-relapsed disease. The likelihood of late relapse is low, but we don’t know that until we get appropriate long-term follow-up.

The other important and timely point is getting good long-term follow up given the recent concerns for things like secondary primary malignancies or the development of T-cell lymphomas that have now been reported with a number of CAR T-cell products. That's going to require ongoing long-term follow up in all these patients receiving CAR T, not just those with CLL.

What does the future hold for CAR T-cell therapy in CLL?

I am very excited about the data [observed from] combining CAR T cells with ibrutinib. We [conducted] a [phase 1] clinical trial [NCT02640209] of patients who had been on ibrutinib for a number of months and had not achieved a CR who were then treated with CAR T cells. [We] found that the response rates were quite high; over 40% of patients had a CR [at 3 months]. Interestingly, most patients had no detectable MRD by high sensitivity testing, suggesting that that many more of these patients may have benefited than the measurements of CR may suggest. Many of those responses were long term and ongoing.

What excites me is the development of therapies that are likely to improve outcomes from where they are now. When CAR T cells work, they’re dramatically effective, but we have to work on ways to try and make them effective for more patients. There are many different approaches being tested in the clinic, [such as] novel CAR constructs that use additional cytokines to enhance the CAR T-cell activity. There are studies testing combination therapies of CAR T cells with other treatments, including BTK inhibitors such as ibrutinib, [or new approaches that will be able to select CAR T cells that may be more active.

Allogeneic CAR T-cell therapy may be another important approach for patients with CLL. Using other CAR modified cell types such as NK [natural killer] cells is also being tested and may have some advantages to other cell therapy approaches. Importantly, these type of studies will all be [not only] applicable to CLL, but to the field of CAR T cells in general. The progress is rapid, and this technology is improving all the time.

What do you want practicing oncologists in the community to take away from your presentation?

Community oncologists and patients need to understand the role of CAR T cells and understand the toxicity, but mostly [need to know] to get patients referred to a center that has expertise in doing this. There are accessibility limitations; we know that there are more patients that we believe should be able to benefit from CAR T than those who get referred, and that there are many patients who may think that it might not be for them [because they] do not have all the information. If a patient has relapsed/refractory disease, refer them to a center with expertise in CAR T-cell therapies. It’s worth at least an opinion.

Another important way to address barriers and accessibility [issues] may be, rather than getting every patient into the major academic center, disseminating this therapy into the communities. We are working with our partners and affiliates to try to be able to administer CAR T in more of a community [setting]. That doesn’t mean that every practice in the country is going to be able to give CAR T, but there are select community hospitals that are not necessarily right at the major academic centers that can develop the expertise to administer CAR T where patients are. We believe this has the potential to dramatically impact access for people who may live too far away from the academic center or too far away from the city.

Reference

US FDA approves Bristol Myers Squibb’s Breyanzi as the first and only CAR T cell therapy for adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). News release. Bristol Myers Squibb. March 14, 2024. Accessed May 20, 2024. https://news.bms.com/news/details/2024/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Breyanzi--as-the-First-and-Only-CAR-T-Cell-Therapy-for-Adults-with-Relapsed-or-Refractory-Chronic-Lymphocytic-Leukemia-CLL-or-Small-Lymphocytic-Lymphoma-SLL/default.aspx