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Two Giants of Hodgkin Lymphoma Research

November 10, 2021

Dr. Margaret Shipp and Dr. Stephen Ansell Honored with the 2021 Ernest Beutler Lecture and Prize

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The Ernest Beutler Lecture and Prize is named after the late Ernest Beutler, MD, past president of ASH and a physician-scientist with a career that spans more than 50 years. It recognizes an individual who has enabled advances in basic science and another who has used clinical science or translational research to transform basic science advances into significant developments in patient care. This year, Margaret Shipp, MD, professor of medicine at Harvard Medical School, Douglas S. Miller Chair in Lymphoma, and director of the Dana-Farber/Harvard Cancer Center Lymphoma Program is recognized with the basic science award, and Stephen Ansell, MD, PhD, who is professor of medicine in the Division of Hematology at the Mayo Clinic and chair of the Mayo Clinic Lymphoma Group, is the translational/clinical awardee.

Dr. Shipp explained that that the work of her group ranges from exploring the basic science of lymphoid malignancies, to translating their findings into clinical trials. The Shipp Lab focuses on aggressive B-cell lymphoma, particularly diffuse large B-cell lymphoma and large B-cell lymphoma subtypes, as well as Hodgkin lymphoma (HL). Working with Dr. Stephen Ansell to characterize the genetic signature of HL, she identified a recurrent alteration — a copy at a specific region chromosome np24.1. They observed that this resulted in increased expression of a ligand for an immunosuppressive pathway, PDFL1, that led to evaluating PD1 signaling as a mechanism of immune evasion in HL, and assessing the activity of PD1 blockade in lymphoma. The group went on to characterize the frequency of the np24 alterations and their prognostic significance, “and more generally, the nature of the immunosuppressive microenvironment in HL,” Dr. Shipp explained. “[This is an] example of a tumor where a genetic alteration actually results in an immune evasion mechanism that can be specifically targeted therapeutically. This has gone from evaluation of PD 1 blockade in patients with relapsed/refractory HL, to evaluation in combination therapies with newly diagnosed HL.”

Dr. Shipp became interested in lymphoid malignancies early on in her medical studies. “There was beginning to be an explosion of knowledge regarding both the normal cell types that contributed to immune response, and in lymphoma, the malignancies that arose from these normal lymphocytes,” she said. Dr. Shipp was convinced that hematologic malignancies was an attractive area of the field that would dramatically change throughout her professional lifetime, and major advances in the understanding of prognosis, diagnosis, and therapy of these diseases would emerge. The passion for learning she felt then remains today as she considers some of the most exciting breakthroughs in the field. “One of the things that is really interesting and unusual about HL,” she said, “is only 1 to 2 percent of the cells are actually malignant cells.” Dr. Shipp further explained that the rest of the lymphoma is made up of an inflammatory immune cell infiltrate that doesn’t work well, which creates, in her words, “a very unusual situation where there seems to be a synergy between this very small number of HL cells [with] the majority of these immune inflammatory cells in the microenvironment.” She stressed the importance of understanding the nature of the immune response or lack thereof in order to appreciate what one can do treatment-wise to change outcomes.

Dr. Shipp made sure to acknowledge the mentors both on the clinical side and the research side throughout her career that she considers role models. She expressed gratitude for having had the opportunity, particularly at a young age, to work directly with them and learn not only about their work but about their methods and approaches to specific areas of research. At Dana-Farber Cancer Institute, where she has spent most of her career, her early mentors like the head of medical oncology Dr. George P. Canellos, a leader in clinical lymphoma, taught her a great deal. On the basic side, she learned from mentors and colleagues like Dr. Frederick W. Alt, Dr. Klaus Rajewsky, and Dr. Stanley J. Korsmeyer.

According to Dr. Shipp, the field of hematology is one where the basic understanding of genetics and biology has led to incredibly meaningful advances in treatment approaches for patients with hematologic diseases. “So, for someone who is interested in having their work really make a difference in patients’ lives, and is also interested in understanding the biology, it’s a wonderful area of investigation and place to devote a career,” she said.

“I have professionally grown up as a member of ASH,” Dr. Shipp concluded, “and have been lucky enough to participate in Society activities throughout my professional career.” Today, upon receiving this award, she feels deeply honored.

Dr. Ansell similarly sees this recognition as an honor, “that was totally unexpected,” he said. He feels humbled to join a list of previous recipients who have contributed so significantly to the understanding and management of patients with blood-related cancers and disorders. He also highlighted how special it is to receive this honor along with Dr. Shipp. Dr. Ansell described his research as focused on understanding the tumor microenvironment in lymphoma and using intratumoral immune cells to effectively target the malignant clone, with a specific interest in developing and optimizing treatment strategies that can eventually eradicate cancer. His group also focuses on intratumoral cells that facilitate the growth of malignancy. “And we strive to develop strategies that inhibit pathways that support cancer cell growth,” he added.

Dr. Ansell developed an interest in treating lymphoma patients after being invited to do a retrospective analysis of the outcome of older patients with lymphoma, treating them in his practice, and becoming involved in clinical trials to optimize their care. “Many research questions subsequently arose from practical issues encountered while treating patients. This taught me to remain inquisitive and ask questions, particularly when results were not as expected,” he explained. “While an activated and effective immune response to hematologic malignancies is our goal, many immunological barriers to an effective immune response are present in cancer patients,” he said. In normal physiology, immune activation is closely controlled by other cells including regulatory T cells that dampen down immune activation to prevent an overexuberant immune system that could cause damage, and activated cells express receptors that allow for them to be suppressed. The cancer cell in lymphoma exploits these pathways by recruiting regulatory cells to the tumor or overexpressing the ligands that signal through inhibitory receptors. “This all results in a very immunologically suppressed tumor environment that prevents the immune system from eradicating the cancer,” Dr. Ansell said, highlighting that this knowledge has allowed for the development of therapies that block inhibitory signals or deplete suppressive cells.

This exciting work and Dr. Ansell’s many discoveries have been made possible in part with help from many colleagues, he emphasized. A medical oncologist in South Africa, Dr. Geoffrey Falkson, helped Dr. Ansell focus on treating patients with lymphoma; Dr. Diane Jelinek, a scientist at the Mayo Clinic, provided research space in her lab and helped him establish a research path. These leaders taught him to expect research to be challenging but to remain optimistic and tenacious in pursuing his goals. Dr. Ansell carried these lessons with him, and today advises junior colleagues entering hematology “to truly embrace the concept of being a lifelong learner.” He added that as the field continues to evolve and change, it is critical to embrace the change and be willing to learn new things every day. “The rapid changes make being part of hematology truly exciting and allow for new insights into disease biology and for the development of new therapies that may improve the outcomes of patients,” he said.

Drs. Margaret Shipp and Stephen Ansell will present their lecture “Checkpoint Inhibitors in Lymphoid Malignancies” on Tuesday, December 14, in the Georgia World Congress Center, Hall C2-C3, and online via the virtual meeting platform.

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