Matthew Cortese, MD, MPH, is an assistant professor in the Department of Medicine–Lymphoma and Department of Cancer Genetics and Genomics at Roswell Park Comprehensive Cancer Center.

Dr Cortese on Future Directions for the Multiomic Investigation of Venetoclax in CLL

“Venetoclax works and repairs the immune system to a degree. Venetoclax monotherapy in [a patient with CLL] who’s very sick all the time would be a reasonable option, [although] an unconventional option [in the context of] looking to extend time to next treatment and progression-free survival. [However, it] certainly is an option and something to be aware of for the future and for research purposes, too.”

Matthew Cortese, MD, MPH, an assistant professor of oncology in the Department of Medicine – Lymphoma and the Department of Cancer Genetics and Genomics at Roswell Park Comprehensive Cancer Center, discussed next steps for the multiomic evaluation of venetoclax (Venclexta) activity in patients with chronic lymphocytic leukemia (CLL).

More research in this area is needed, Cortese emphasized. However, Cortese stated that the work that has been done already has identified both germline and somatic mutations that may be clinically relevant in smaller patient subgroups. Notably, study findings in larger cohorts are less influenced by genomic variability, which may affect the reliability of observed results, he explained.

Research efforts at Roswell Park are actively expanding in this area, according to Cortese. He helped design and implement an automatic consent protocol, which allows patients with newly diagnosed CLL the option to contribute to research by donating surplus blood samples—specimens that would otherwise be discarded. This facilitates the development of CAR T cells and enables comprehensive multiomic analyses across a broad patient population, he noted. Although funding for this research remains a challenge, Roswell Park investigators are seeking support through industry partnerships, grants, and collaborative efforts with other institutions to validate these findings.

Venetoclax continues to be a cornerstone of standard-of-care treatment for patients with CLL and appears to exert a restorative effect on immune function, Cortese said. Although venetoclax monotherapy may not be a conventional treatment option for these patients, it may be rational in patients with significant comorbidities or immunologic compromise, although its use must be considered within the context of goals prolong progression-free survival and delay the need for subsequent therapy, he reported. Therefore, venetoclax monotherapy remains an important therapeutic consideration for CLL, particularly in the context of ongoing clinical research, he concluded.

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Matthew Cortese, MD, MPH, discusses the next steps for the multiomic evaluation of venetoclax activity in chronic lymphocytic leukemia.

Dr Cortese on Potential Mechanisms for Improving CLL Outcomes With Venetoclax

“I wanted to…look at patients…with CLL who receive venetoclax in a standard-of-care setting to see if we could tease apart…the beneficial immunologic effects of that treatment.”

Matthew Cortese, MD, MPH, an assistant professor of oncology in the Department of Medicine – Lymphoma and the Department of Cancer Genetics and Genomics at Roswell Park Comprehensive Cancer Center, discussed the ways that his research goals informed the rationale for conducting a multiomic analysis investigating the immunologic activity of venetoclax (Venclexta) in patients with chronic lymphocytic leukemia (CLL).

Cortese works in the lab of Francisco Hernandez -Ilizaliturri, MD, at Roswell Park Comprehensive Cancer Center, where Cortese’s goal is to investigate ways to improve treatments for patients with this disease. Hernandez-Ilizaliturri’s lab focuses on studying venetoclax in cell lines.

Cortese and other CLL experts presented findings from their research at the 

. One abstract presented at the conference showed preliminary evidence that venetoclax treatment improves T-cell function, a finding that may influence future clinical trials and translational research, Cortese explained. Cortese’s own presentation at the meeting focused on outcomes of patients with CLL who received venetoclax in the standard-of-care setting. Cortese and colleagues aimed to identify potential immunologic effects of the agent that are beneficial to patients, he said.

This study showed that venetoclax can repair immune synapses in patients with CLL using mechanisms that are more complex than simply eliminating malignant CLL cells. Additionally, venetoclax repairs several immune compartments—including T cells, natural killer cells. Furthermore, venetoclax treatment induced T-cell repair mechanisms, such as shifting T cells from terminally differentiated or exhausted states toward “stem-like” states. These changes may explain why CAR T-cell toxicities were enhanced in ex vivo/in vitro killing assays that the investigators performed on cell lines. Investigators plan to validate these findings in future research that is ongoing or in development stages.

Matthew Cortese, MD, MPH, discusses the rationale for an analysis of the immunologic activity of venetoclax in patients with chronic lymphocytic leukemia.

Dr Cortese on Methods for Evaluating immunologic Changes With Venetoclax in CLL  

"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."

Matthew Cortese, MD, MPH, an assistant professor of oncology in the Department of Medicine–Lymphoma and the Department of Cancer Genetics and Genomics at Roswell Park Comprehensive Cancer Center, details the methods employed to conduct a multiomic analysis of immunologic changes in chronic lymphocytic leukemia (CLL) following treatment with venetoclax (Venclexta).

, demonstrated that treatment with venetoclax at 400 mg daily was associated with immune synapse repair through complex immunomodulatory mechanisms beyond the cytotoxic clearance of malignant CLL cells. Cortese began by stating that this analysis incorporated a multiomic approach to assess the effect of venetoclax on immune cell function in 13 patients with CLL who had completed the study and reached the 400-mg daily target dose of venetoclax. Peripheral blood samples were collected within 24 hours prior to treatment initiation and again on day 30, immediately following the standard ramp-up to the target 400-mg daily dose, he described.

Multiomic analyses included bulk RNA sequencing, peripheral blood mononuclear cell RNA sequencing, T-cell sequencing by negative selection, epigenomic profiling, and methylomic analysis using reduced representation bisulfite sequencing, he noted. These analyses assessed transcriptomic and epigenetic changes relevant to gene regulation, Cortese explained.

Additionally, flow cytometric evaluation using an institutional immune reconstitution panel—originally developed for use in post-allogeneic stem cell transplantation—was employed to assess T-cell and natural killer (NK) cell function, macrophage activation, and stemness markers, Cortese continued. Results showed that after adjusting for treatment response at day 30, T cells, NK cells, and macrophages demonstrated evidence of repair and functional reconstitution, Cortese concluded.

Matthew Cortese, MD, MPH, discusses the methods used to produce a comprehensive map of immune changes that occur with venetoclax treatment in CLL.

Dr Cortese on Methods for Evaluating immunologic Changes With Venetoclax in CLL

Matthew Cortese, MD, MPH, discusses the benefit of analyzing multiple biological layers when identifying immunologic changes in CLL after venetoclax.

Dr Cortese on the Benefits of a Multiomic Evaluation of Immunologic Changes in CLL After Venetoclax

“[If there are] methyl groups added onto the DNA that can block transcription, [it can] further affirm that [we’re] seeing a true biological signature. It’s going through a multiomic sandwich, and it self-validates without many patient samples needed, which I think is really cool.”

Matthew Cortese, MD, MPH, an assistant professor in the Department of Medicine–Lymphoma and Department of Cancer Genetics and Genomics at Roswell Park Comprehensive Cancer Center, discusses the benefits of a multiomic evaluation of immunologic changes in a smaller patient population of patients with chronic lymphocytic leukemia (CLL) following treatment with venetoclax (Venclexta).

 demonstrated that treatment with venetoclax was associated with immune synapse repair with complex mechanisms beyond clearance of malignant CLL cells. The bioinformatic process of multiomics integrates data from several biological layers into a comprehensive model. Specifically, after covariate adjustment for treatment responses at 30 days, T cells, natural killer cells, and macrophages were repaired after treatment with venetoclax at 400 mg daily in patients with CLL (n = 13).

Although the analysis only included 13 patients with CLL, the process of multiomics self-validates itself without the need for a larger patient population, Cortese begins. A benefit of multiomics includes layering several data streams simultaneously, he explains. For example, when signals of 1 BCL2 gene emerge from the data streams, it can be found in the transcriptomic profile, which shows where BCL2 is located in the pathway map, he says. When these are linked to metabolites that offshoot from the respective pathway, all changes within the data streams are shown, he adds.

Furthermore, these streams allow for the evaluation of methylation, groups of which can be added to the DNA and block transcription, according to Cortese. The entire process further affirms a true biological signature and helps establish all of the layered data streams, he concludes.

Dr Cortese on the Role of Venetoclax in CLL Immune Synapse Repair 

“We normalized our results based on lymphocyte count reduction, evaluating white blood cell count, tumor burden by physical exam, and CT imaging. Although imaging was part of standard care, only approximately half of the patients underwent elective scans. After normalization, immune repair effects remained significant despite covariate adjustment."

Matthew Cortese, MD, MPH, assistant professor, Department of Medicine–Lymphoma, and Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, discusses the immunologic changes observed with venetoclax (Venclexta) treatment in patients with chronic lymphocytic leukemia (CLL).

findings from an analysis presented at the 2024 ASH Annual Meeting

 further studies with larger patient cohorts are necessary to determine the extent to which venetoclax contributes to immune restoration, Cortese begins. Looking ahead, he suggests that patients with CLL requiring CAR T-cell therapy may benefit from prior treatment with BCL-2 inhibitors in combination with T-cell–engaging therapies to enhance treatment outcomes. He notes that although CAR T-cell therapy has demonstrated efficacy in large B-cell lymphoma, its activity in CLL has been less pronounced. However, opportunities exist to optimize these approaches for CLL, he says.

Specifically, findings from the analysis demonstrated that multiple immune compartments, including T cells, natural killer cells, and macrophages, exhibited repair following treatment with venetoclax in patients with CLL. Notably, these immune modifications remained significant following covariate adjustment for treatment responses at 30 days post-treatment.

A deeper understanding of the interactions between cancer and the immune system will facilitate the development of improved treatment strategies in clinical practice, particularly for B-cell malignancies where T-cell–engaging therapies are under investigation.

Cortese concludes that although further research is needed, identified germline and somatic mutations may have greater relevance in smaller patient cohorts. As cohort size decreases, genetic confusion diminishes, leading to more confident results. Ongoing research will focus on patients receiving standard-of-care venetoclax to further refine these findings.

Matthew Cortese, MD, MPH, discusses the immunologic changes observed with venetoclax in patients with CLL.

Matthew Cortese, MD, MPH

Articles

Dr Cortese on Future Directions for the Multiomic Investigation of Venetoclax in CLL

Dr Cortese on Potential Mechanisms for Improving CLL Outcomes With Venetoclax

Dr Cortese on Methods for Evaluating immunologic Changes With Venetoclax in CLL

Dr Cortese on the Benefits of a Multiomic Evaluation of Immunologic Changes in CLL After Venetoclax

Dr Cortese on the Role of Venetoclax in CLL Immune Synapse Repair