Francisco J. Hernandez-Ilizaliturri, MD is a professor of oncology in the Department of Medicine – Lymphoma, director of the Lymphoma Research, head of the Lymphoma Translational Research Lab, associate professor in the Department of Immunology, at Roswell Park Comprehensive Cancer Center; and clinical professor in the Department of Medicine at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo in New York. 

Francisco J. Hernandez-Ilizaliturri, MD, details the clinical implications of venetoclax for the treatment of patients with CLL regarding T-cell repair. 

Dr Hernandez-Ilizaliturri on the Implications of Immunologic Changes With Venetoclax in CLL

“Clinically, we do hope that patients who have CLL…and [require] CAR T-cell therapy [could potentially receive] combined BCL-2 inhibitors with T-cell engaging therapy as a way to improve the success that we’re seeing with this particular class of agents.”

Francisco J. Hernandez-Ilizaliturri, MD, professor, oncology, Department of Medicine – Lymphoma, director, Lymphoma Research, head, Lymphoma Translational Research Lab, associate professor, Department of Immunology, Roswell Park Comprehensive Cancer Center; clinical professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, details the clinical implications of immunologic changes observed with venetoclax (Venclexta) treatment in patients with chronic lymphocytic leukemia (CLL).

, more studies with a larger patient population need to be conducted to further identify whether venetoclax contributes to T-cell repair, Hernandez-Ilizaliturri begins. Looking forward, he notes that patients with CLL who require CAR T-cell therapy will hopefully have the potential to be treated with BCL-2 inhibitors with T-cell engaging therapy to improve the success of treatment outcomes. He emphasizes that although CAR T-cell therapy has shown great efficacy in patients with large B-cell lymphoma, the activity has not been as robust for patients with CLL. However, there is a margin to further improve this for those with CLL, he says.

Specifically, the findings from the analysis demonstrated that multiple immune compartments, such as T cells, natural killer cells, and macrophages, were repaired after treatment with venetoclax in patients with CLL. Of note, these repairs remained following the covariate adjustment for treatment responses at 30 days after treatment.

Having a deeper understanding of the interaction between cancer cells and the immune system will allow further development of treatment strategies to implement in clinical practice, especially for patients with B-cell malignancies regarding T-cell engaging therapy, Hernandez-Ilizaliturri concludes.

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Dr Hernandez-Ilizaliturri on Immunologic Changes in Venetoclax-Treated CLL

“BCL-2 inhibition with venetoclax could be… used to further enhance the T-cell function of patients, and it can potentially be used to enhance CAR T-cell therapy options, or other T-cell engaging options, for patients with CLL and perhaps other types of lymphomas.”

Francisco J. Hernandez-Ilizaliturri, MD, professor, oncology, Department of Medicine – Lymphoma, director, Lymphoma Research, head, Lymphoma Translational Research Lab, associate professor, Department of Immunology, Roswell Park Comprehensive Cancer Center; clinical professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, discusses findings from a multiomic study investigating immunologic changes in patients with chronic lymphocytic leukemia (CLL) who received treatment with venetoclax (Venclexta).

This study found that patients with CLL exhibit T-cell exhaustion, characterized by impaired T-cell function, which likely contributes to their susceptibility to infections and secondary cancers, Hernandez-Ilizaliturri begins. This study showed that treatment with venetoclax, a BCL-2 inhibitor, improved T-cell fitness within 1 month of therapy initiation. This improvement included metabolic reprogramming, where T cells shift to using lipids for energy production—a process associated with enhanced immune responses, he explains.

Additionally, treatment with venetoclax was shown to induce surface changes on T cells, priming them for improved cytotoxic activity against infectious agents and potentially against cancer cells as well, Hernandez-Ilizaliturri notes. A killing assay using standard cell lines showed that T cells that were engineered into CAR T cells after 1 month of venetoclax exposure demonstrated significantly enhanced in vitro lymphoma cell killing efficiency compared with untreated T cells.

These findings indicate that BCL-2 inhibition with venetoclax targets malignant cells and rejuvenates the immune system by enhancing T-cell function, Hernandez-Ilizaliturri emphasizes. This dual mechanism of action positions venetoclax as a potential adjunctive therapy that may improve outcomes with CAR T-cell therapy or other T-cell–engineered immunotherapies in patients with CLL and other lymphomas, he concludes.

Francisco J. Hernandez-Ilizaliturri, MD, discusses findings from a study investigating immunologic changes in patients with CLL treated with venetoclax.

Dr Hernandez-Ilizaliturri on Selecting Between CAR T-Cell Therapies for FL

Francisco Hernandez-Ilizaliturri, MD, professor, oncology, Department of Medicine—Lymphoma; director, Lymphoma Research, head, Lymphoma Translational Research Lab; associate professor, Department of Immunology, Roswell Park Comprehensive Cancer Center; clinical professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, discusses factors that inform optimal CAR T-cell therapy selection for patients with follicular lymphoma (FL).

Two CAR T-cell therapies are currently FDA approved for the treatment of patients with FL. In 2021, 

 (Yescarta) for the treatment of adult patients with relapsed/refractory FL who have received at least 2 prior lines of therapy. In 2024, 

the FDA granted accelerated approval to lisocabtagene maraleucel

The selection of CAR T-cell therapy for patients with FL varies across institutions and is influenced by several factors, including product availability, safety profiles, and patient-specific considerations, Hernandez-Ilizaliturri begins. Different institutions may have different levels of experience with each CAR T-cell product, leading oncologists to favor one product over another based on their familiarity and their institutions’ established protocols, Hernandez-Ilizaliturri says.

Patient characteristics, such as age, comorbidities, tumor burden, and the urgency of treatment play a significant role in determining the most appropriate CAR T-cell product for each patient, Hernandez-Ilizaliturri notes. For example, some emerging CAR T-cell therapies have shorter manufacturing times, which may be advantageous for patients with high tumor burdens or those requiring prompt intervention, he explains. Conversely, patients with lower tumor burdens but higher comorbidity risks may benefit from receiving a CAR T-cell product with a longer manufacturing process that offers a more favorable safety profile, according to Hernandez-Ilizaliturri.

Given these variables, there is no one-size-fits-all answer to which CAR T-cell product is ideal for the management of FL, he reports. This decision is highly individualized and depends on the patient’s clinical situation and the available resources at the treating institution, he says. Furthermore, the expertise an institution’s health care team has administering specific CAR T-cell therapies can influence the choice of treatment, as the training required for administering different products may vary, Hernandez-Ilizaliturri concludes.

Francisco Hernandez-Ilizaliturri, MD, discusses factors that inform the selection of CAR T-cell therapies for patients with follicular lymphoma.

Dr Hernandez-Ilizaliturri on the Use of CAR T-Cell Therapy in R/R Multiple Myeloma

Francisco Hernandez-Ilizaliturri, MD, director, Lymphoma Research, professor, oncology, Department of Medicine, head, Lymphoma Translational Research Lab, associate professor, Department of Immunology, Roswell Park Comprehensive Cancer Center; clinical professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, discusses the use of CAR T-cell therapy in patients with relapsed/refractory multiple myeloma.

the FDA indication for ciltacabtagene autoleucel (cilta-cel; Carvykti) was expanded

 to include patients with relapsed/refractory multiple myeloma who have received 1 prior line of therapy, supported by data from the phase 3 CARTITUDE-4 trial (NCT04181827). 

The FDA also expanded the indication for idecabtagene vicleucel (ide-cel; Abecma)

 in April of 2024 to include patients with relapsed/refractory multiple myeloma who have received at least 2 prior lines of therapy, based on findings from the phase 3 KarMMa-3 trial (NCT03651128).

These expanded indications represent significant advancements in the management of multiple myeloma and demonstrate the potential of these innovative immunotherapies beyond their initial application in B-cell lymphomas, Hernandez-Ilizaliturri begins. These products are a promising treatment option for younger patients with good renal function who require effective disease control, he says.

However, data from the CARTITUDE-4 and KarMMa-3 trials indicate shorter durations of response (DOR) with cilta-cel and ide-cel, respectively, compared with the DOR that is typically seen with these products in B-cell lymphomas, Hernandez-Ilizaliturri explains. This shorter DOR in multiple myeloma indicates the importance of early intervention, as the efficacy of CAR T-cell therapy may diminish in patients with heavily pretreated, compromised immune systems, he emphasizes.

Additionally, the trial findings underscore the necessity of understanding how myeloma cells may impair CAR T-cell function, highlighting the need for further research to enhance the efficacy of these therapies, Hernandez-Ilizaliturri notes. The encouraging results from these trials are poised to influence clinical practice, yet they also raise important questions that necessitate collaboration between industry and academic centers to develop improved CAR T-cell products tailored for patients with multiple myeloma, Hernandez-Ilizaliturri concludes.

Francisco Hernandez-Ilizaliturri, MD, discusses the use of CAR T-cell therapy in patients with relapsed/refractory multiple myeloma.

Dr Hernandez-Ilizaliturri on CAR T-Cell Therapy vs Bispecific Antibodies in DLBCL

Francisco Hernandez-Ilizaliturri, MD, director, Lymphoma Research, professor, oncology, Department of Medicine, head, Lymphoma Translational Research Lab, associate professor, Department of Immunology, Roswell Park Comprehensive Cancer Center; clinical professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, discusses 

factors to consider when deciding between CAR T-cell therapies or approved bispecific antibodies

 for patients with diffuse large B-cell lymphoma (DLBCL).

When deciding between CAR T-cell therapy and approved bispecific antibodies for managing DLBCL, several factors must be considered, Hernandez-Ilizaliturri begins. Bispecific antibodies are a form of T-cell engager therapy with demonstrated efficacy in clinical trials for relapsed/refractory large-cell lymphoma, follicular lymphoma, and, to a lesser extent, other types of lymphomas, he says. Some bispecific antibodies are specifically approved for patients with relapsed/refractory large-cell lymphoma, Hernandez-Ilizaliturri explains, adding that therefore, weighing the choice between CAR T-cell therapy and bispecific antibodies is crucial in this context.

CAR T-cell therapy has the advantage of longer follow-up data, providing evidence that it can potentially cure approximately 30% to 40% of patients with relapsed or refractory LBCL, he continues. This longer follow-up period allows for a more robust understanding of the therapy’slong-term efficacy, according to Hernandez-Ilizaliturri. In contrast, the follow-up data for bispecific antibodies are not as extensive, making it less clear whether patients are being cured with this treatment, Hernandez-Ilizaliturri states.

For younger and more fit patients, CAR T-cell therapy might be preferable due to the extensive follow-up data and the hematology field’s increased proficiency in managing acute toxicities associated with this treatment, which helps mitigate some concerns, Hernandez-Ilizaliturri explains. However, for frailer patients, bispecific antibodies may be a more appropriate option, he elucidates.

Geographic location and access to CAR T-cell therapy also play a significant role in treatment selection, Hernandez-Ilizaliturri expands. Bispecific antibodies offer the advantage of being administered closer to the patient’s home, provided the physician is comfortable with their use and capable of monitoring the associated adverse effects, he notes. This convenience can be particularly beneficial for patients who live far from specialized treatment centers offering CAR T-cell therapy, Hernandez-Ilizaliturri concludes.

Francisco Hernandez-Ilizaliturri, MD, discusses deciding between CAR T-cell therapies or approved bispecific antibodies for diffuse large B-cell lymphoma.

Francisco Hernandez-Ilizaliturri, MD discusses the implications of Liso-Cel in the context of relapsed or refractory follicular lymphoma

Francisco Hernandez-Ilizaliturri, MD, director, Lymphoma Research, professor, oncology, Department of Medicine, head, Lymphoma Translational Research Lab, associate professor, Department of Immunology, Roswell Park Comprehensive Cancer Center; clinical professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, discusses the clinical implications of the FDA’s approval of lisocabtagene maraleucel (liso-cel; Breyanzi) for the treatment of patients with relapsed or refractory follicular lymphoma.

the FDA granted accelerated approval to liso-cel

 for use in adult patients with relapsed or refractory follicular lymphoma who have previously received at least 2 lines of systemic therapy.

Hernandez-Ilizaliturri notes that one of the most interesting aspects about this particular CAR T-cell therapy is its safety profile. Compared with other CAR T-cell therapies, liso-cel is associated with a lower incidence and severity of cytokine release syndrome (CRS) and neurotoxicity, he explains. These characteristics are particularly advantageous as they potentially enhance the feasibility of its use in a broader patient population, including those with preexisting comorbidities.

This safety profile contributes to better patient tolerance and aligns with clinical goal of reducing treatment-related complications, which can be severe and life-threatening in the context of potent cellular therapies like CAR T-cell therapy, Hernandez-Ilizaliturri says. The reduction in severe adverse effects (AEs) such as CRS and neurotoxicity can significantly influence treatment decisions, offering a viable option for patients who might otherwise be considered at higher risk for such AEs.

The accelerated approval of liso-cel for patients with relapsed or refractory follicular lymphoma highlights the agent’s impact across the treatment landscape for a variety of B-cell malignancies, Hernandez-Ilizaliturri explains. In relapsed or refractory settings, where treatment options may be more limited, the approval of liso-cel underscores the importance of the ongoing development and evaluation of therapies that could provide effective disease control with manageable safety profiles in later lines of treatment, he concludes.

Dr Hernandez-Ilizaliturri on the Implications of the FDA Approval of Liso-Cel for R/R Follicular Lymphoma

Francisco Hernandez-Ilizaliturri, MD, discusses the potential advantages of iopofosine I 131 in Waldenström macroglobulinemia.

Dr Hernandez-Ilizaliturri on the Potential Advantages of Iopofosine I 131 in Waldenström Macroglobulinemia

Francisco Hernandez-Ilizaliturri, MD, director, Lymphoma Research, professor, oncology, Department of Medicine, head, Lymphoma Translational Research Lab, associate professor, Department of Immunology, Roswell Park Comprehensive Cancer Center; clinical professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, discusses the unique potential advantages of the radiotherapeutic iopofosine I 131 (formerly CLR 131) compared with other available agents for patients with Waldenström macroglobulinemia.

Iopofosine I 131 was initially evaluated in the phase 2 CLOVER-1 trial (NCT02952508) across various B-cell malignancies. In this trial, the agent displayed notable efficacy and safety signals for heavily pretreated patients with Waldenström macroglobulinemia. These findings prompted the initiation of the CLOVER-WaM expansion cohort within the study for patients with Waldenström macroglobulinemia.

Initial data from the expansion cohort demonstrated durable responses and a tolerable safety profile for iopofosine I 131 in this population, according to Hernandez-Ilizaliturri. Despite the limited duration of follow-up, ongoing observations indicate that responses may continue to improve over time, even months after treatment completion, potentially providing iopofosine I 131 with a notable advantage over current therapies, Hernandez-Ilizaliturri states.

Distinguishing features of iopofosine I 131 include its novel mechanism of action and finite treatment duration, contrasting with continuous therapies, such as BTK inhibitors, Hernandez-Ilizaliturri explains. Despite producing deep responses, iopofosine I 131 offers the potential for treatment completion, which may be preferable for certain patients, he adds.

Safety data from 44 patients with Waldenström macroglobulinemia receiving iopofosine I 131 revealed that hematologic toxicities associated with the agent were primarily grade 1/2, with some instances of grade 3 or higher anemia or neutropenia, Hernandez-Ilizaliturri continues. Importantly, these adverse effects (AEs) were reversible, he adds. Unlike other available agents for patients with Waldenström macroglobulinemia, no vascular or renal AEs were reported with iopofosine I 131, he notes. These preliminary efficacy and safety findings underscore the favorable profile of this novel therapeutic option for patients with Waldenström macroglobulinemia, Hernandez-Ilizaliturri concludes.

Francisco Hernandez-Ilizaliturri, MD, discusses the unique potential advantages of the radiotherapeutic iopofosine I 131 in Waldenström macroglobulinemia.
 

Francisco Hernandez-Ilizaliturri, MD