Venetoclax Elicits Immune Synapse Repair in Chronic Lymphocytic Leukemia

Treatment with venetoclax (Venclexta) could repair immune synapses in patients with chronic lymphocytic leukemia (CLL) via complex, multifaceted mechanisms beyond clearance of malignant CLL cells, according to Matthew Cortese, MD, MPH.

Preliminary findings from an analysis presented at the 2024 ASH Annual Meeting demonstrated that multiple immune compartments—including T cells, natural killer cells, and macrophages in CLL—were repaired in patients with CLL following treatment with venetoclax, and that these repairs remained after covariate adjustment for treatment responses at 30 days post-treatment.

“Venetoclax can essentially be used as a partner with immunotherapies, cellular therapies like bispecific [antibodies] and CAR T-cell therapy, and others, maybe checkpoint inhibitors for [patients with] Richter transformation; all those [combinations] can be investigated in the future to help patients,” Cortese said during an interview with OncLive® at the meeting.

In the interview, Cortese discussed the methods used in the analysis, key findings, and the future implications of the research.

Cortese is an assistant professor in the Department of Medicine-Lymphoma and the Department of Cancer Genetics and Genomics at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

OncLive: What methods were used in this analysis for evaluating immunologic changes in CLL with venetoclax?

Cortese: We evaluated baseline specimens within 24 hours prior to the initial dose of standard-of-care [SOC] venetoclax given by standard ramp[-up dosing] to a target dose of 400 mg per day, [which is the dose on the] label for the FDA approval of venetoclax for CLL. We [also] collected peripheral blood specimens at day 30, after the completion of that venetoclax ramp-up [period], at usually the first day or two of the 400-mg dose for patients. [With that sample], we did a comprehensive multiomic analysis.

We conducted both bulk and peripheral blood mononuclear cell RNA sequencing, as well as some T-cell sequencing by negative selection. We performed a comparative analysis, [and] we also did transcriptomics with RNA sequencing, epigenomics, and methylomics with reduced representation bisulfite sequencing. This assesses where methyl groups are sitting on portions of the genome and may regulate transcription, then eventually translation.

We evaluated flow cytometric data as well. We have an in-house immune reconstitution panel. It looks at T-cell function and K-cell function, stemness markers, and macrophages. We use [the panel] for inpatient cellular therapy and bone marrow transplant, as well as post-allogeneic [stem cell] transplant, which was where it was originally designed [to be used]. We’ve applied [that panel to this research].

What were some of the key findings from this study that were presented at ASH?

What we presented at ASH was a comprehensive map of all these pathways: what’s turned on and what’s not turned on [with venetoclax treatment]. [We also investigated] multiple immune cell subsets, specifically focusing on T cells, but we also studied macrophages, K cells, and a smattering of other [subsets] as well. In essence, venetoclax appears to repair the immune system.

CLL, when it’s growing and proliferating, causes immunosuppressive effects, so we try to control those [during treatment]. We normalized our results by reduction in the lymphocyte counts. We evaluated white blood cell counts [and] tumor bulk in patients by exam and CT scans, which were kind of the SOC. [However,] approximately half of our patients [underwent elective] imaging. When we normalized those results, those immune repair effects remained and persisted despite the covariate adjustment.

Finally, [we also] built CAR T cells out of patients’ isolated blood—so ex vivo CAR T-cell production—which was kind of an axicabtagene ciloleucel (Yescarta)–like construct that uses a] CD8 zeta costimulatory domain [and targets] CD19, just like all the commercial [CAR T-cell] products. [We] showed that cytotoxicity is enhanced in most patients [who receive] venetoclax treatment.

What is your main message for colleagues based on the findings from this evaluation?

For one, this is a preliminary [investigation]; we had 13 patients, [which] is not a lot. One of the benefits of multiomics is you can layer data streams over each other, and when you see signals emerge on your transcriptomic profile, like BCL-2 in this case, then you know where BCL-2 lives on a pathway map. You can link it to metabolites that are known to offshoot from that pathway. You see those all changes together, and you know it’s a true signal. Then, you can even evaluate methylation if there are methyl groups added onto the DNA that can block transcription [to] further affirm that you’re seeing a true biological signature. This “multiomic sandwich” self-validates without that many patient samples needed, which is cool.

There’s much more work that needs to be done. There are germline mutations and other somatic mutations that we’ve picked up, which are going to be more effective in a small patient cohort. The more patients you have, the less some of the genetic noise fades into the background. It gives you even more confident results. We’re going to be doing much more research in more patients who are continuously receiving SOC venetoclax.

Venetoclax works to repair the immune system to a degree, so venetoclax monotherapy would be a reasonable treatment option in a patient who’s sick all the time. [It would be] an unconventional option, [because] you’re also looking to extend time to next treatment and progression-free survival, but [it] is an option to consider for the future and for research purposes, too.

Reference

Cortese MJ, Wright JP, Mavis C, et al. Multiomic evaluation of immunologic changes in chronic lymphocytic leukemia with venetoclax treatment. Blood. 2024;144(suppl 1):78. doi:10.1182/blood-2024-212019