Editor's Note: The 2025 Chinese Society of Clinical Oncology (CSCO) Annual Meeting was grandly held in the golden autumn season, gathering top experts from the global field of oncology. In the lymphoma session, the renowned American scholar, Professor Owen O'Connor, delivered a splendid presentation on the topic "REASONS FOR OPTIMISM IN TREATING THE T-CELL MALIGNANCIES: A BIOLOGICAL BASIS COMES INTO FOCUS." He systematically reviewed the historical challenges in the treatment of T-cell lymphoma and emphatically elaborated on why epigenetic targeting will be the key to turning the tide, pointing to a hopeful new path for the future treatment of this disease. 

As a highly heterogeneous group of malignant tumors, the treatment of T-cell lymphoma has seen slow progress over the past few decades, leading to pessimism among countless clinicians. However, at the beginning of his report, Professor O’Connor clearly stated that although there is no new data that can immediately change clinical practice, “we are beginning to see the light at the end of the tunnel.”

[The Historical Dilemma and Paradigm Reflection in T-cell Lymphoma Treatment]

Professor O’Connor began by candidly analyzing the sources of the long-standing pessimism in the field. He pointed out that for decades, with very few exceptions, the natural history of T-cell lymphoma has not been fundamentally altered. There is a lack of recognized standard-of-care chemotherapy regimens for both first-line and relapsed/refractory stages. Even the Echelon-2 study, which changed the treatment model for anaplastic large cell lymphoma (ALCL), represents a rare success story.

More frustratingly, almost all known biological targets in cancer have been explored with little success. Many drugs that once held great promise, such as Romidepsin, were ultimately withdrawn from the market by the U.S. Food and Drug Administration (FDA) because its randomized controlled trial failed to demonstrate a benefit when combined with the CHOP regimen.

“One of the major mistakes we made was to simply combine promising new agents with CHOP-based chemotherapy,” emphasized Professor O’Connor. “Adding a new drug to the four-drug CHOP regimen almost always results in greater toxicity, but with the exception of the data for Brentuximab Vedotin in ALCL, there have been few success stories.” Taking Romidepsin as an example, in the RO-CHOP study, its dose intensity had to be reduced by nearly 50% to manage toxicity, which fundamentally limited the efficacy of the targeted drug.

The professor concluded: “A failed clinical trial design does not equal a failed drug. We need smarter trial designs to help these promising drugs truly benefit patients.”

[Dispelling the Clouds: The Epigenetic “Achilles’ Heel” of T-cell Lymphoma Becomes a New Focus]

After deep reflection, Professor O’Connor turned the topic towards a hopeful future. He firmly proposed that a large body of evidence indicates T-cell lymphomas have a unique biological vulnerability—epigenetic regulation.

“I can assert that among all cancers, no disease is as sensitive to epigenetic targeting as T-cell lymphoma,” said Professor O’Connor. Epigenetics is a complex system that regulates gene expression, primarily involving “writers” (e.g., histone acetyltransferases), “erasers” (e.g., histone deacetylases, HDACs), and “readers” (e.g., BET proteins). These enzymes work in concert to precisely control the switching on and off of genes by altering the open or condensed state of chromatin.

Professor O’Connor listed a multi-dimensional chain of evidence to prove that T-cell lymphoma is a classic “epigenetic disease”:

Genomic Evidence: Numerous studies have identified a massive number of epigenetic driver gene mutations in the genomes of peripheral T-cell lymphomas (PTCL).

Drug Approval Evidence: Among the drugs approved globally for the treatment of T-cell lymphoma, those targeting epigenetics (such as HDAC inhibitors) are predominant. It is noteworthy that a total of four histone deacetylase (HDAC) inhibitors have been approved for treating T-cell lymphoma worldwide, a phenomenon unseen in any other type of tumor.

Preclinical Model Evidence: In mouse models, introducing epigenetic gene mutations found in human patients through genetic engineering can successfully induce T-cell lymphoma in mice, perfectly recapitulating the human disease.

Emerging Target Validation: In addition to HDACs, drugs targeting DNA methylation (e.g., azacitidine) and EZH2 (Enhancer of zeste homolog 2) have also shown remarkable activity. For example, the monotherapy overall response rates (ORR) for the EZH2 inhibitors Valemetostat and SHR2554 have reached approximately 44% to 60%.

[From “Good Drugs” to “Using Drugs Well”: Nanotechnology Overcomes Pharmacological Bottlenecks]

Although epigenetic drugs show great promise, their clinical application is still limited by suboptimal pharmacokinetic properties. Professor O’Connor pointedly noted: “Most existing epigenetic drugs have extremely short half-lives (measured in minutes or hours), high plasma protein binding, chemical instability, and in vivo drug exposure (area under the curve, AUC) far below the concentration (IC50) required to achieve ideal tumor suppression.”

Taking Romidepsin as an example, its once-weekly dosing schedule means the drug is almost completely cleared from the body by dinnertime on the day of administration, giving tumor cells a full week to “recuperate,” which greatly limits the sustainability of its gene expression regulation.

To overcome this fundamental obstacle, Professor O’Connor’s team has dedicated the past several years to a revolutionary technological innovation—using nanoparticle delivery technology to optimize epigenetic drugs. This achievement was recently published in the top-tier international journal, Blood.

The technology utilizes high-molecular-weight polymers to construct nano-micelles that encapsulate drug molecules. Its advantages are exceptionally prominent:

Dramatically Increased Drug Exposure: Compared to the naked drug, the nano-formulation can increase the drug’s AUC by up to 30-fold and extend its half-life by 4-5 times.

Tumor-Selective Accumulation: Through specially designed nanocarriers, the drug can accumulate precisely in tumor tissues with minimal distribution to other organs. Fluorescence tracing experiments clearly show that the drug is almost entirely concentrated at the tumor site.

Significantly Enhanced Efficacy with No Additional Toxicity: Despite the tens-fold increase in drug exposure, no corresponding increase in toxicity was observed. In mouse models of T-cell lymphoma and adult T-cell leukemia/lymphoma (ATL), the nano-drug demonstrated unprecedented tumor suppressive effects, significantly extending the overall survival of the models.

“We believe that by improving the pharmacological properties of epigenetic drugs, we can truly unlock their full therapeutic potential,” Professor O’Connor stated excitedly. “We have successfully prepared nanoparticles of azacitidine and an EZH2 inhibitor, and the next step will be to explore combination therapies with these optimized drugs.”

[Expert Outlook: Co-creating a New Future for T-cell Lymphoma Treatment]

Looking to the future, Professor O’Connor expressed that the poor prognosis of T-cell lymphoma may not stem from its complex biology itself, but from our past flawed treatment strategies. Now, we must “follow the science,” shifting from simply adding new drugs to conventional chemotherapy to rational combinations based on biological mechanisms.

He specifically mentioned that the nanodrugs developed by his team are planned for clinical trials and expressed a strong desire to collaborate with Chinese colleagues, including Professor Jun Ma, to synchronously introduce this cutting-edge research to China, allowing patients worldwide to benefit as soon as possible.

This report not only injects a powerful boost of confidence into the struggling field of T-cell lymphoma treatment but also demonstrates the immense energy that can be unleashed when basic scientific innovation (like nanomedicine) is closely integrated with clinical problems. From reflecting on failures to focusing on core biological mechanisms, and then using cutting-edge technology to overcome pharmacological challenges, Professor O’Connor has outlined a clear and hopeful path forward. As advocated by the conference, the fusion and collaboration of global wisdom will undoubtedly accelerate the process of conquering the significant challenge of T-cell lymphoma.

Contribution/Interview Source: Oncology Outlook – Oncology News