Epigenetic Priming and Immunotherapy Synergy Across the Lymphoma Space

The treatment landscape for lymphoma is becoming increasingly defined by the integration of laboratory-driven insights into clinical practice. Research at Columbia University is uncovering how epigenetic modifications can be harnessed not only to stop cancer growth but to strip away the cloaking mechanisms that allow lymphoma cells to evade the immune system. By combining epigenetic drugs with immunotherapy, clinicians are exploring ways to upregulate ancient viral genes—endogenous retroviruses—and antigen-presenting proteins, making tumors more visible to the body’s natural defenses.

In a discussion with CancerNetwork^® at Columbia University, Jennifer Effie Amengual, MD, outlined several pivotal trials, including those combining tazemetostat (Tazverik) with belinostat (Beleodaq) for T-cell lymphomas and the phase 2 SWOG S2207 trial (NCT05890352) focused on chemotherapy-free backbones for large B-cell lymphoma.^1,2 These strategies prioritize efficacy while carefully managing treatment-related adverse effects through biologically targeted precision.

Additionally, Amengual addressed the unique challenges of managing HIV- and Epstein-Barr virus (EBV)–related malignancies, where immunosuppression and complex drug interactions necessitate meticulous clinical care. As the field moves toward pairing immune-based treatments with molecularly targeted agents, the primary focus remains on overcoming therapy resistance and tailoring interventions to the specific biological drivers of each patient’s disease.

Amengual is the Herbert Irving Associate Professor of Medicine in the Division of Hematology and Oncology of the Center for Lymphoid Malignancies and Hebert Irving Comprehensive Cancer Center at Columbia University Irving Medical Center.

CancerNetwork: What ongoing clinical trials in lymphoma are you currently involved with? Are there any novel therapeutic strategies undergoing evaluation that hold particular promise for treating patients with lymphoma?

Amengual: We are so fortunate at Columbia to be involved with and leading a whole host of clinical trials that target the spectrum of lymphoma subtypes. Lymphoma is a very heterogeneous disease, and we have clinical trials that are working for many of these subtypes.

One I would like to highlight is a trial we are leading that is looking at 2 epigenetic drugs, tazemetostat and belinostat, in relapsed/refractory lymphomas. This work was developed in my laboratory, where we looked at the preclinical application of this combination. Some lymphomas harbor mutations in epigenetic controls—which change how genes are expressed—and these tend to cluster in certain subtypes of lymphoma, especially those in the germinal center. We had this idea: can we target multiple epigenetic pathways to synergize these effects in these specific lymphomas?

Based on our work in the lab, we combined tazemetostat and belinostat and found very strong synergy in certain lymphoma subtypes, and we were able to bring this study to the clinic. This is funded through the NCI and Cancer Therapy Evaluation Program [CTEP], and it is open nationally. So far, we have found that it is a very well tolerated combination, and we are seeing an enrichment of responses in T-cell lymphomas, so we are excited for the next steps. This is nearing completion of enrollment, and hopefully, we will have some signal of response that we can present soon.

Another clinical study we are very excited about, which we are leading nationally, is the SWOG 2207 study. This is a clinical trial for relapsed/refractory large B-cell lymphoma for patients who are not eligible for stem cell transplant. We are looking at using the tafasitamab-cxix [Monjuvi] and lenalidomide [Revlimid] backbone, which is a chemotherapy-free backbone for this patient population, and then layering biologically targeted agents onto it such as zanubrutinib [Brukinsa], which is a BTK inhibitor, or tazemetostat, which is an EZH2 inhibitor.

We are using biologically targeted agents to try to improve on this backbone while maintaining a strong safety signal and reducing toxicities that might be seen with chemotherapy. So far, we are almost complete with the safety run-in, and we have found no unexpected toxicities. We are excited to open this up to the randomized portion of the study. Again, it is open nationally because we are seeing an exciting early signal of response; these are in patients who are heavily pretreated, many of whom have had CAR T-cell therapy and bispecific antibodies and have done quite well with the 3-drug combinations.

Finally, I would like to switch gears altogether and highlight a study that we have spearheaded here at Columbia that is trying to alter the way we care for patients with post-transplant lymphomas. This is a rare disease, but patients who undergo organ transplantations have been increasing in numbers over the years due to improved technologies and how transplants occur; based on that, we are starting to see increased numbers of post-transplant lymphomas.

We are working in collaboration with Stanford University to identify novel biomarkers of response using circulating tumor DNA (ctDNA) for post-transplant lymphomas, look at new ways to stratify risk in patients, and [develop] new treatment regimens for those who are newly diagnosed. This is very exciting. We are looking at a number of factors that can change the way we treat patients with post-organ transplant lymphomas in the future. This is just a small snapshot of some of the trials we have here at Columbia, and we are excited that we are leading the way with many of these entities.

Based on your work, how does epigenetics overlap with immune surveillance and endogenous retroviral expression in the setting of lymphoma? How can these observations be translated into actionable clinical strategies?

In our laboratory, we have been very interested in studying epigenetic therapies, which are broad treatments that work to alter how genes are expressed without changing the genes themselves. What we found by evaluating these therapies is that they can impact immune evasion and how immune therapies respond to lymphomas. One hallmark feature of some lymphomas is that they can hide themselves from the immune system. They do this by downregulating proteins on their surface through which other immune cells can recognize and destroy them.

Some of these proteins that get expressed on the surface are considered endogenous retroviruses. Endogenous retroviruses are ancient viral genes that have been incorporated into our own DNA over time. They are typically suppressed in our biology, but some become expressed. When they do, they can create new targets for immunotherapy to recognize malignancies. We believe that epigenetic therapies might upregulate endogenous retroviral peptides or proteins on the surface of cancer or lymphoma cells and allow immunotherapy to better recognize them.

We have also seen that epigenetic drugs such as tazemetostat and belinostat can upregulate key antigen-presenting proteins, such as MHC class I and II antigens, on the surface of lymphoma cells, while making them better recognizable to the immune system. We found that these drugs do not just work on the lymphoma cells themselves but can work on the tumor microenvironment (TME). Using these drugs, we are able to activate the T cells in the peripheral immune environment and make them more responsive to the lymphoma itself. This can be used to prime immunotherapies that rely on healthy T cells to fight the lymphoma.

Coming full circle, we have drugs that target the biologic underpinnings driving the lymphoma while increasing immune visibility to our immune system and activating our innate T-cell immunity. When we combine epigenetic therapies with immunotherapy, we find robust synergy in preclinical models of lymphoma. We are excited to be collaborating with [researchers at] Cornell, who found similar findings on a clinical trial that is using the epigenetic drug tazemetostat to prime a bispecific antibody, mosunetuzumab-axgb [Lunsumio]. We are actively enrolling patients on this study for those with newly diagnosed follicular lymphoma, and we are finding the combination to be safe so far. We are collecting correlative studies so that we can show what we have seen in the laboratory regarding increased T-cell activity and increased expression of antigens on B cells occurring in patients themselves.

What are some current challenges associated with the management of HIV- and EBV-related hematologic illnesses, and how can clinicians optimize their treatment decision-making among these patient populations?

Patients with HIV are at an increased risk for developing lymphoma, and this is in part due to the virus leading to impaired T-cell immunity; they are at risk of developing oncogenic viral illnesses such as EBV, which can drive the development of lymphoma.

EBV-related lymphomas not only occur in those with HIV but also in those on other immunosuppressive therapies such as organ transplants, those with autoimmune phenomena, those on biologic agents, and sometimes in [patients who are older]. EBV-associated lymphomas tend to be more aggressive than those that are not associated with EBV.

What further complicates treatment for these patients is that they are often on many drugs or therapies that can have interactions with the chemotherapies we use to treat the lymphomas. We take this into account very carefully. We work with our pharmacy colleagues to ensure that there are no drug-drug interactions and to pick the right medications for these patients that are safe in combination.

In addition, because patients with HIV or EBV-related lymphomas tend to have immunosuppression, they are more likely to develop complications from chemotherapy, such as infections. We often need to go slowly and then increase our doses very [gradually] to ensure safety as we proceed with treatment. There is very fine micromanagement that occurs when we are treating patients both with HIV or EBV-related lymphomas so that we can precisely use the right medications and the right doses to safely and effectively eradicate the lymphomas.

Looking ahead, where do you think the field should head to further bolster patient outcomes in lymphoma?

Right now, we have had an explosion of immunotherapies for lymphoma—whether it is bispecific antibodies, CAR T-cell therapy, or checkpoint blockade—which have made a real impact on the outcomes and care for those with lymphoma.

What we need to do now is first try to understand how we can best incorporate these [therapies] when patients are newly diagnosed. Another thing we need to evaluate is that these therapies are often agnostic to the biology of what is driving the disease. We need to figure out how we can best pair these therapies with targeting molecular drivers of disease. These therapies work very well, but they do not work or induce complete remissions in everyone.

Perhaps by targeting these immunotherapy approaches while simultaneously targeting the molecular drivers of disease, we can get at both mechanisms of cancer to better impact their efficacy. In addition, we have to figure out why some people are not responding. There are some lymphomas that tend to be resistant to some of these immunotherapies, and we do not quite have a handle on why that is yet. Understanding resistance mechanisms to immunotherapies will allow us to fine-tune how we use these treatments and find ways to prevent and overcome resistance, which will bring those immunotherapies even further in impacting patient care.

References

1. Amengual JE, Tun AM, Piorczynski TB, et al. Etctn P10500: Phase 1 study of tazemetostat plus belinostat for the treatment of relapsed or refractory lymphoma. Blood. 2024;144(suppl 1):3112. doi:10.1182/blood-2024-199650
2. Amegual JE, Li H, Reagan PM, et al. S2207: Randomized phase II study of the addition of targeted agents to tafasitamab-lenalidomide in transplant ineligible patients with relapsed/refractory LBCL. Blood. 2024;144(suppl 1):3123.2. doi:10.1182/blood-2024-199784