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Hastening the Development of Novel Therapies for Peripheral T-Cell Lymphomas


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Peripheral T-cell lymphomas (PTCLs) make up a small fraction of all non-Hodgkin lymphomas—just 15%—in the United States.1 Although rare in the United States, the incidence of PTCL is common across Asia, the Caribbean, and sub-Saharan Africa. Although the reason for such global variation in PTCL is not fully understood, studies indicate that infection with human T-lymphotropic virus type 1 and Epstein-Barr virus may play a role in the development of specific subtypes.2,3

Owen A. O’Connor, MD, PhD

Owen A. O’Connor, MD, PhD

To hasten advances in the treatment of rare T-cell lymphomas, earlier this year, Owen A. O’Connor, MD, PhD, Professor of Medicine and Experimental Therapeutics; Director of the Center for Lymphoid Malignancies; and Co-Program Director of the Lymphoid Development and Malignancy Program at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, and his colleagues Won Seog Kim, MD, PhD, Professor of Hematology/Oncology at Samsung Medical Center in Seoul, Korea, and Pier Luigi Zinzani, MD, PhD, Professor of Medicine at the University of Bologna in Italy, launched the Global T-Cell Lymphoma Consortium. This international network of community and university cancer centers is dedicated to accelerating the accrual of patients with T-cell lymphomas to clinical trials to advance effective treatments for these morphologically and molecularly disparate diseases.

Won Seog Kim, MD, PhD

Won Seog Kim, MD, PhD

Pier Luigi Zinzani, MD, PhD

Pier Luigi Zinzani, MD, PhD

This past April, Dr. O’Connor was awarded the American Cancer Society (ACS) Clinical Research Professorship, a 5-year $400,000 grant, which he plans to use to support the mission of the Global T-Cell Lymphoma Consortium as well as to increase basic research at Columbia University.

Recently, The ASCO Post talked with Dr. O’Connor about the launch of the Global T-Cell Lymphoma Consortium, the future direction of research in T-cell lymphomas, as well as the prospect of changes in the standard of care for these rare lymphomas and improvements in survival rates.

Leveraging New Classes of Drugs

Why did you and your colleagues decide to launch the Global T-Cell Lymphoma Consortium?

The three of us represent areas of the world most affected by T-cell lymphomas, including Asia, Europe, and North America. Our mission is to provide a comprehensive network of clinical cancer centers and investigators with specialized expertise in T-cell lymphoma with the tools necessary to conduct quality clinical research to advance the standard of care for patients with these cancers. The primary objective of the consortium is to accelerate patient accrual to clinical studies to hasten the development of novel treatments or treatment platforms to improve outcomes. My institution is acting as the coordinating site; so far, we have about 20 sites open globally, and our goal is to expand that number.

Using what we have learned about how to target tumor biology more precisely has led us away from the conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy regimen in the treatment of T-cell lymphoma to more targeted therapies, such as the histone deacetylase (HDAC) inhibitors. Our plan is not to do CHOP-addition studies, which have dominated the field for nearly 2 decades and have not produced tangible improvement in patient outcomes. We want to leverage new classes of drugs in a way that hopefully changes the natural history of these diseases.

We are about to launch two clinical studies—one at Columbia University Medical Center and one in Seoul, South Korea—investigating immune epigenetic platforms. We are also about to launch a website where patients will be able to find clinical trials accruing near where they live, as well as educational material about their specific type of T-cell lymphoma. In addition, we are also building a section for physicians on new therapies being developed and investigated.

Because T-cell lymphomas represent a heterogeneous and rare group of diseases of about 30 subtypes, there is an absolute need to quicken the pace of patient accrual into clinical studies. In the past, the problem has been that because there are so few patients diagnosed with these lymphomas, it’s been difficult to accrue them into clinical trials; consequently, we haven’t been able to get the data we need to learn about the efficacy and safety of new therapies. Having an international consortium will enable us to accelerate a global collaborative effort to harmonize patient accrual and try to answer specific clinical questions more expeditiously. We will also be generating tissue and blood specimens to study disease pathogenesis as well as prognostic and predictive biomarkers.

Our goal is to replace platinum chemotherapies, which haven’t been effective in PTCL. In our laboratory, we are looking at drug combinations that are biologically rational and T-cell–selected to build novel doublets and triplets, which will challenge the results we typically see with CHOP chemotherapy.

“We have learned that T-cell lymphoma is not B-cell lymphoma and that therapies developed for B-cell lymphoma don’t work in T-cell lymphoma.”
— Owen A. O'Connor, MD, PhD

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Molecular Pathogenesis

What are you learning about the biology of T-cell lymphoma? Why are patient outcomes so inferior compared with B-cell lymphoma? 

We have learned that T-cell lymphoma is not B-cell lymphoma and that therapies developed for B-cell lymphoma don’t work in T-cell lymphoma. They are two radically different diseases, at least predicated on their sensitivity to chemotherapy. We have also learned from a better understanding of the underlying molecular pathogenesis that these two types of lymphomas are radically different at the gene-expression level and that there are big differences in the genetic-expression profiles among the many subtypes of T-cell lymphomas.

Data continue to emerge showing that T-cell lymphomas may be among the more prototypic epigenetic diseases. Through our work and the work of others, we have learned that combinations of epigenetic drugs, including not just the HDAC inhibitors, but the hypomethylating agents as well, have a profound synergistic effect on the disease in preclinical models and in the clinical setting. We are seeing profound activity with these combinations in heavily pretreated patients.

Unfortunately, just about 20% of patients with T-cell lymphoma can expect some type of long-term survival with current therapies. There is still little consensus about what the right front- or second-line and beyond therapy should be.

All the international and national guidelines on T-cell lymphomas have subtle differences in their treatment recommendations, because we don’t have enough data to be dogmatic about one approach over another. And this chaos is not going to be resolved by investigating new combinations of chemotherapy alone. We will resolve the chaos by understanding the biology of these diseases and the merits of the drugs we have and how best to use them in more effective combinations.

“If we can increase patient accrual by just 10% to 20%, we will be moving much more expeditiously down the path of identifying more effective treatment for [T-cell] lymphomas.”
— Owen A. O'Connor, MD, PhD

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Global Variation

T-cell lymphoma is more common in Asia, the Caribbean, and sub-Saharan Africa than in the United States. Why is there such global variation?

There isn’t one answer about why there is such geographic variability. We do know that T cells are incredibly promiscuous when it comes to invasion or allowing invasion by viruses, such as the human T-lymphotropic virus type 1 retrovirus, which is endemic in places such as Kyushu, Japan.

What we are interested in learning in the lab is whether treatment of T-cell lymphomas with various epigenetic drugs massively upregulates a whole host of cancer testis antigens and cancer neoantigens, including many viral antigens. We believe it is the induction of those cancer antigens on the surface of the T cells that will enhance their recognition by immune surveillance and, theoretically, enhance their possible eradication with immune checkpoint inhibitors.

Overcoming Diagnostic Difficulties

How difficult is it to diagnose T-cell lymphoma?

Often, pathologists confuse T-cell lymphoma with a completely different entity, such as Hodgkin disease, a B-cell non-Hodgkin lymphoma, or an epithelial cancer. But more frequently, the diagnosis of the subtype is wrong, which may not have clinical implications, given we don’t currently treat subtypes differently. There are some exceptions, such as ALK-positive anaplastic large cell lymphoma, which is a highly curable disease with CHOP-based chemotherapy, as is ALK-negative anaplastic large cell lymphoma with the DUSP22 mutation; so, some subtypes may respond to CHOP therapy.

Anaplastic large cell lymphomas are often confused with Hodgkin lymphoma because of the expression of CD30. Where there are questions or uncertainty about the exact T-cell lymphoma subtype or the diagnosis, it is not unreasonable to confirm the pathologic diagnosis at a center with T-cell lymphoma expertise, although, admittedly, there are not many of these centers. Whether an accurate diagnosis impacts outcome depends on the subtleties of each subtype differentiation.

And this uncertainty brings up the absolute need to put every patient with T-cell lymphoma into a clinical trial. If we can increase patient accrual by just 10% to 20%, we will be moving much more expeditiously down the path of identifying more effective treatment for these lymphomas.

Future Treatment Direction

What will future treatment look like for T-cell lymphoma?

The future treatment of these diseases will likely follow the paradigms that pioneered breakthrough research in multiple myeloma. I think the backbone of future treatment paradigms in T-cell lymphomas will rely on immune epigenetic drugs. And that could mean any number of therapies, ranging from the integration of immune checkpoint inhibitors, novel antibody-drug conjugates such as brentuximab vedotin (Adcetris) targeting CD30 or other novel antibody-drug conjugates targeting CD37, to other new biologics, such as the anti–CD47-based therapies being developed or the bispecific antibodies targeting both CD30 and CD16A.

“We are anxious to see whether CAR T-cell therapy could be effective in CD30-positive T-cell lymphoma.”
— Owen A. O'Connor, MD, PhD

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Although we don’t have our drug equivalent of a rituximab (to target CD20 in T-cell lymphoma) or an antibody or biologic with one reliable target, there are a host of emerging targets. Having that knowledge will mean a major advance in therapies going forward.

The epigenetic piece of new therapies refers to leveraging the synergistic interactions we see with drugs such as the HDAC inhibitors and the hypomethylating agents. New data suggest that the antifolate pralatrexate (Folotyn) has significant epigenetic effects against relapsed or refractory peripheral T-cell lymphoma, which distinguishes it from methotrexate. There may be a strong biologic rationale and a strong synergistic molecular rationale for combining these drugs with immunologic therapies to improve outcomes. We are studying in the lab how the integration of different classes of agents might be effective in T-cell lymphomas.

And, of course, adoptive T-cell therapies remain an exciting research area, as does chimeric antigen receptor (CAR) T-cell therapy in lymphoma. We are anxious to see whether CAR T-cell therapy could be effective in CD30-positive T-cell lymphoma.

We need to capitalize and build on the research momentum happening in peripheral T-cell lymphoma through increased patient accrual into clinical trials. Then we can change the natural history of these lymphomas and improve life expectancy for the thousands of patients diagnosed with the disease each year.

DISCLOSURE: Dr. O’Connor has financial relationships with Spectrum Pharmaceuticals, Millennium Pharmaceuticals, Seattle Genetics, Celgene, TG Therapeutics, and Agensys.

REFERENCES

1. Adams SV, Newcomb PA, Shustov AR: Racial patterns of peripheral T-cell lymphoma incidence and survival in the United States. J Clin Oncol 34:963-971, 2016.

2. Kanno H, Kojya S, Li T, et al: Low frequency of HLA-A*0201 allele in patients with Epstein-Barr virus-positive nasal lymphomas with polymorphic reticulosis morphology. Int J Cancer 87:195-199, 2000.

3. Tajima K, Hinuma Y: Epidemiology of HTLV-I/II in Japan and the world. Gann Monogr Canc Res 39:129-149, 1992.


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