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Novel Therapies to Increase Durable Remission Rates for T-Cell Lymphoma

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000550407.47818.5f
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T-cell lymphoma

T-cell lymphoma

“I am my mother's son,” said a reflective Samuel Ng, MD, PhD, Instructor of Medicine at Harvard Medical School, as well as Attending Physician in the Lymphoma Program of the Division of Hematologic Malignancies and a researcher exploring the biology of T-cell lymphomas at Dana-Farber Cancer Institute, Boston.

Though he was born in Boston, Ng moved with his family to Arizona when he was 5. “My mom took a job in Phoenix running a senior citizen center. She organized meals for the elderly, helped them to find essential services, drove them to medical appointments, and more. Every time we went out to a restaurant someone would come up and thank her for something she'd done. It left a big impression on me; it made me want to help people when I can.”

With an interest in science, Ng received a full scholarship from the Flinn Foundation to the University of Arizona where he studied molecular and cellular biology. After his junior year, he spent a summer at NIH and worked, for the first time, with a physician scientist.

“It was one of the most formative experiences of my life,” Ng told Oncology Times. There he had the rare opportunity to work in the lab of Michael Lenardo, MD, and was mentored by Richard Siegel, MD, PhD, who later became Chief of Autoimmunity at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“It was inspirational. Mike's lab conducted research on apoptosis and basic molecular defects that could cause T cells to die improperly,” he noted. “Furthermore, in clinic I saw that some patients would be actively studied at NIH and, in some cases, would experience improved health thanks to the work being done. It deeply attracted me toward a dual path. I already had known I wanted to do medicine at some level, but once I saw the direct application of research, I was really hooked.”

After graduating, Ng attended Harvard Medical School where he worked with his mentor, Katia Georgopoulos, PhD, to understand how earliest stem cells become specified in the bone marrow in mice. “I also worked to understand how the Ikaros gene regulates that process. It was a time when I learned how immune cells—B cells and T cells—really work and how to do very rigorous science,” Ng recalled.

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A T-Cell Research Path

Since earning a PhD and MD, Ng has forged a career that includes a half-day each week treating patients with non-Hodgkin lymphoma, Hodgkin lymphoma, and chronic lymphocytic leukemia at Dana-Farber, with the rest of his professional time devoted to the “rigorous science” he came to love.

Displaying particular passion when discussing his work with T-cell lymphomas, Ng explained, “When I was first a resident here working in clinic, I could see there was not much we could offer T-cell lymphoma patients. There were few novel therapies as compared to B-cell lymphomas. In general T-cell lymphoma patients have outcomes that are much worse than those of B-cell lymphoma patients. The durable remission rate for T-cell lymphoma patients is generally less than 30 percent, which compares non-favorably to B-cell non-Hodgkin lymphoma where even the highest risk group in diffuse large B-cell lymphoma, the most common subtype, sees a durable remission rate around 50 percent. Whenever I wasn't up to my eyes with clinical work, I would take the opportunity to read about the biology of T-cell diseases and I realized there wasn't much that was known. I knew there was a clear need and opportunity for research in T-cell lymphoma. I wanted to pursue it.”

Samuel Ng, MD, PhD

Samuel Ng, MD, PhD

Ng was quick to count his blessings when it comes to his professional home that would help him pursue his interests. “I want to acknowledge my overall environment and the clinical group that has supported me and allowed me to work in the clinic and bring insights from the clinic to my research, and vice versa. ‘Patient care’ is not just lip service here. My mentor, David Weinstock, MD, has been incredibly generous and has put me in touch with wonderful people who help me with my research.”

Describing the focus of that research, Ng said, “I have a two-fold approach to my own work. One big element is to understand how recurrent genetic mutations found in T-cell lymphoma patient samples alter the molecular biology of normal T cells,” he explained.

“And I continue to explore apoptosis—cell death. It is a fundamental process with fundamental questions I am aiming to answer: What happens when immune cells die improperly? How that might contribute to T-cell transformation? When a non-malignant T-cell transforms to become a lymphoma cell, the mechanisms by which some T cells are governed—those that tell it when to die and those that tell it when not to proliferate—have definitely gone askew.”

Ng said he hopes to eventually find “... a rational mechanism for targeting mutations found in T-cell lymphoma. Right now I am working to understand how mutations in the TET2 gene determines how genes are turned off and turned on in the T cell to contribute to T-cell lymphoma, and why a mutation [RhoA G17V] in the gene called RhoA is found in 60 percent of patients with angioimmunoblastic T-cell lymphoma (AITL).

In the lab, Ng has indeed generated a mouse model that expressed the RhoA G17V mutation in CD4 T cells. “These mice did in fact develop autoimmunity—inflammation that would cause fibrosis in their ears and tails, and we also observed unregulated production of antibodies that caused kidney damage to these mice. This is intriguing because frequently you see immune dysregulation in patients with AITL, and this deserves further study. I am also studying AITL-like tumors that develop in these mice.”

The second leg of his work is focused on discovering and confirming novel genes that could be targeted by new therapeutic approaches, by using existing T-cell lymphoma models.

“I am doing this work with my mentor, David Weinstock, and my colleagues, Raphael Koch, MD, and Noriaki Yoshida, MD, PhD. We published a paper (Nat Commun 2018;9(1):2024) that provides genomic profiles of more than 20 T-cell lymphoma models, as well as a list of genes that might be targets for new therapies,” explained Ng. “We made all of the data publicly available through an open source journal in the hopes of catalyzing additional interest in the wider community for this approach to lymphomas with that platform.”

Asked to describe what his research “looks like,” Ng answered, “It looks like a standard biology lab from the surface, and uses mouse models. But the work is unique. We use cell tissues from mice, as well as tissues from immunocompromised mice in which we have implanted T-cell lymphoma tumor cells. Those are known as patient-derived xenograft (PDX) models. There the tumor cells can grow and we can reuse these as a source for additional experiments.”

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Exploiting PDX Models

Ultimately, Ng and colleagues aim to develop novel therapies that improve outcomes for patients afflicted with T-cell lymphoma. As for the aforementioned afflicted mice, “...we have been able to use a compound, ALRN-6924. We saw that when genes called MDM2 or MDMX were deleted in T-cell lymphoma cell lines, the cell lines would die. MDN2 works by upregulating; its normal function is to degrade the tumor suppressor TP53. So when you get rid of MDM2, TP53 is more stable. Thus it can sense a lot of the molecular abnormalities that might exist in the lymphoma cell and switch on an apoptotic pathway.

“We hope we can trigger this with ALRN-6924, which is in phase I clinical trials right now. There are efforts to see how a combination of this drug with frontline cytotoxic chemotherapies might enhance that overall effect. We are further testing it in preclinical models and so far the data looks promising.”

This is just one example of how Ng expects using T-cell lymphoma cell lines with treatments in the PDX models can advance the field. “Further, we can take the tissue from the PDX models, and work with statisticians and computationalists to understand how these tissues might be affected by a drug,” Ng said. “We can then go back to the lab and do additional testing in the PDX models, refine what we think is going on, and possibly combine this drug with other existing therapies to advance a novel concept.”

Even when not in the lab or clinic, Ng finds ways to utilize science to advantage. Married, with two young children, (a son, 7, and daughter, 4) Ng said, “Though work is very frequently on my mind, I try to stay involved with my wife and my kids. I try to let a little bit of what I do in the lab inform my interactions with the children a little bit. We keep a community garden vegetable plot, and I explain to them about how they can take little seedlings and have them become productive beanpoles or tomato plants. I try to teach them that timing matters, and that they need to water them and do various things to help them thrive. It's like wet lab research,” he added with a laugh. “I hope they are getting it.”

Drawing a big picture of T-cell understanding in the lymphoma environment, Ng said, “We often use B-cell non-Hodgkin lymphoma as a lens through which we try to understand T-cell non-Hodgkin lymphoma. We use essentially the same chemotherapy backbone to treat both despite the fact there are many elements of transformation that are unique to T-cell lymphoma. T-cell lymphomas are rarer than B-cell lymphomas, and that's probably for a reason. T cells orchestrate the overall immune response, so they are more tightly regulated than B cells.

“Understanding specific mechanisms that are important for their regulation is what we, as a field, need to concentrate on and certainly what I, as an investigator, have been exploring. At the beginning I was doing careful study of recurrent mutations in T-cell lymphoma that have only become apparent to us through sequencing efforts over the last 5 years, and that is a good starting point.

“Yet at the same time, because patients with these diseases have such a dire need of new therapies, I realize more agnostic approaches—like using chemical genetic screens on the T-cell lymphoma cell line panel—is warranted. Finding vulnerabilities through these large-scale screening techniques is valuable even if we don't understand right away what the mechanisms might be,” Ng detailed.

“My hope is that by using both agnostic and targeted approaches in the future and beginning to understand how these pathways are altered, they might dovetail to reveal that there are common pathways that T cells travel down to become lymphoma cells,” Ng noted further. “When we find those pathways, we will also discover ways to block them or drugs to keep cells from becoming lymphoma. If we can find more common pathways that are misregulated and used by T cells to become lymphoma cells, we might be able to more broadly treat T-cell lymphoma.”

A longer-term fond ambition of Ng's is to understand T cell-lymphoma well enough to bring contributions from the setting of lymphoma to general T-cell biology, “...and to understand how T cells are prevented from becoming autoimmune cells. That is a hope I hold very dear,” he added.

So what would spell career success for this clinician/emerging investigator? After a momentary pause, he answered, “Every patient is important. My hope is that we can improve on that less-than-30 percent rate of durable remission for patients with T-cell lymphoma. But even a modest improvement—5 percent, 10 percent, whatever it might be—would be what I would consider a success. It would make all of this effort worthwhile. However, I would not declare victory at that point. I would continue to work and push that rate to 100 percent. That's the goal.”

Valerie Neff Newitt is a contributing writer.

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