Shipp’s Passion Leads to Transformative Research, Innovations in Lymphoma

Margaret A. Shipp, MD

Whenever Margaret A. Shipp, MD, encounters a medical student or young professional seeking career advice, she asks them a simple question. “It’s a matter of trying to understand where people see themselves,” she said. “What is the thing that they’re most excited about? Then [they must] think about how to make that happen.”

Regarding her own career, it’s safe to say that Shipp found her passion and made it happen. Shipp, who now serves as the Douglas S. Miller Chair in Lymphoma, chief of the Division of Hematologic Neoplasia at Dana-Farber Cancer Institute, and a professor of medicine at Harvard Medical School in Boston, Massachusetts, was recognized as the 2024 Giant of Cancer Care inductee in lymphoma. After determining early in life that a hematologic oncology career was her calling, Shipp never looked back.

“I was lucky, as a medical student, to be exposed to people who were just beginning to do some of the early work to elucidate the interactions [of malignant and normal hematopoietic cells], and that influenced my decisions about going into medical oncology and to come to Dana-Farber,” Shipp said. “It was one of the places [where] the early work was beginning to develop and [they were laying] down the benchmarks for the field.”

Shipping Up to Boston

Once she arrived at Southern Methodist University in Dallas, Texas, Shipp did not hesitate in selecting a path toward medical school. After graduating with 2 bachelor’s degrees in biology and English, she received her medical degree from Washington University School of Medicine in St Louis, Missouri, in 1979.

As a medical student, Shipp was exposed to professors running investigative programs in the hematology space. In turn, she worked with scores of patients with hematologic malignancies, and all the signs in front of Shipp steered her toward the lymphoma field.

“[During] medical school, I felt that in my professional lifetime, our understanding of the biology of normal and malignant hematopoietic cells—specifically lymphoid cells—would increase, and that would translate into an improved understanding of lymphomas and more effective targeted therapy,” Shipp said.

Before moving to the East Coast, Shipp remained at Washington University, where she completed her internship and residency at Barnes Hospital. Ultimately, her desire to build on the early work she was exposed to in the hematology field led her to Dana-Farber Cancer Institute.

“When I was looking for fellowships, some of the most exciting work was going on in tumor immunology at Dana-Farber on characterization of normal and malignant lymphocyte subsets and the biology of those subsets,” Shipp said. “I knew at that point I wanted to specialize in lymphoma, so that was particularly attractive to me. The other thing about Dana-Farber that I was excited [about] at that point—and something I continue to be excited [about]—is this real commitment to translational research.”

As Shipp’s career progressed in Boston, she launched the Shipp Laboratory at Dana-Farber Cancer Institute. The group’s mission centers around characterizing molecular signatures and underlying genetic aberrations, subtype-specific survival pathways, and potential therapeutic targets across a range of hematologic malignancies, including diffuse large B-cell lymphoma (DLBCL), LBCL subtypes, and classical Hodgkin lymphoma.¹

In the infancy of her professional life, this was the type of research Shipp dreamed of pursuing. She explained that at the start of her career, multiagent chemotherapy served as the primary treatment for many patients with lymphoma. This drove her passion to better define the genetics and various subtypes of lymphoma to advance novel therapeutic development.

“Treatment approaches were not necessarily based on an understanding of the genetics or the biology of the different lymphoid malignancies,” Shipp said. “The understanding of biology and genetics in my professional lifetime has transformed how we think about treatment approaches, even to a much greater extent than I would have anticipated when I started my career.”

Changing the Lymphoma Landscape

In the lab, Shipp and colleagues found that Reed-Sternberg cells exploited the PD-1 pathway to evade immune detection in classic Hodgkin lymphoma. Additionally, chromosome 9p24.1 alterations were associated with an increased abundance of PD-L1 and PD-L2 ligands, supporting the rationale to investigate PD-1 inhibition as a treatment option for patients with classic Hodgkin lymphoma. Shipp helped develop pilot studies investigating immune checkpoint inhibitors in this patient population.²

In an initial phase 1/2 trial (NCT01592370) of PD-1 blockade, nivolumab (Opdivo) elicited an overall response rate (ORR) of 87% in patients with heavily pretreated Hodgkin lymphoma (n = 23), including a complete response (CR) rate of 17% and a partial response (PR) rate of 70%. In the 13% of patients who did not respond, all had stable disease.

These data led to the registrational phase 2 CheckMate 205 trial (NCT02181738), which evaluated nivolumab in patients with pretreated Hodgkin lymphoma. In patients (n = 80) whose disease did not respond to prior autologous stem cell transplant (ASCT) and either relapsed after or did not respond to brentuximab vedotin (Adcetris), treatment with nivolumab led to an ORR of 66.3% (95% CI, 54.8%-76.4%), including respective CR and PR rates of 9% and 58%.³

In May 2016, findings from CheckMate 205 helped support the FDA’s accelerated approval of nivolumab for the treatment of patients with classical Hodgkin lymphoma that has relapsed or progressed after ASCT and posttransplant brentuximab vedotin.⁴

Shipp noted that similarly successful trials were also performed with a second PD-1 antibody—pembrolizumab (Keytruda)—in patients with relapsed/refractory Hodgkin lymphoma.

“More recently, we’ve incorporated PD-1 blockade as part of first-line therapy [in Hodgkin lymphoma], and we have been gratified to see that the combination of PD-1 blockade with first-line therapy seems to be not only more effective but also less toxic,” Shipp said. “The idea of identifying a genetic alteration in the laboratory, using those insights to translate into a treatment approach, and evaluating the efficacy of that treatment approach—first in patients who had progressed following standard therapies, then increasingly at earlier time points in therapy, [to prevent] relapse rather than treat relapse—has been tremendously rewarding.”

On a broader scale, Shipp’s work has contributed to the risk classification and therapeutic strategies for patients with various lymphomas. Shipp and colleagues published the International Prognostic Index (IPI) for aggressive lymphomas in The New England Journal of Medicine in 1993.⁵

“The IPI has [stood] the test of time. It is used in most prospective, randomized trials to stratify risk and ensure balance between groups,” Ann S. LaCasce, MD, MMSc, of Dana-Farber Cancer Institute, wrote in Haematologica in 2023.⁶ “In nearly all retrospective analyses, the IPI is an independent prognostic factor for progression-free and overall survival on multivariate analysis.”

Shipp explained that her group has long had an interest in DLBCL, and the known heterogeneity and various subtypes of the disease sparked the goal of developing the IPI for this patient population to aid in trial design, risk stratification, and therapeutic development. Shipp credited one of her early mentors, George P. Canellos, MD, of Dana-Farber Cancer Institute, and a 2020 Giant of Cancer Care inductee in lymphoma, with supporting the collaborative effort to develop the IPI in lymphoma.

“The question was: Could we understand bases for that heterogeneity [in DLBCL]? When you’re treating patients, you want to know how likely the treatment that you’re proposing is going to work so patients who have a poor prognosis with standard therapies might have the option of newer experimental therapies at an earlier time point,” she said. “Similarly, patients who are likely to do well with our standard therapies would not be subjected to risks associated with novel therapies.”

More recently, Shipp and colleagues defined genetic based for recognized clinical heterogeneity in DLBCL, providing a framework for specific targeted therapy.⁷

The Rest Is Still Unwritten

Moving across the country tends to be a little easier when you’ve got company. Shipp met Timothy Ernst, MD, during her internship and residency at Barnes-Jewish Hospital, and the 2 married. Shipp and Ernst accepted fellowships at Dana-Farber and completed their training together. Ernst currently practices in hematology and oncology at Mass General Cancer Center at Newton-Wellesley Hospital. The couple has 2 children, Sarah and Katherine.

Although Shipp quipped that one of the reasons she stayed at Dana-Farber for so long was that she simply never left the building, she also dedicated time to helping women of all ages find opportunities to develop their skills and pursue careers in the medical field and beyond. “In terms of broader community impact, one of the areas that is most important to me as a woman in medicine is [finding] opportunities that are available for women and girls in terms of education, training, and professional options. I’ve been involved in organizations related to that [effort],” she said.

Within lymphoma, similar to how Canellos served as one of her early mentors, Shipp said she hopes to do the same for others hoping to break into the space and build on the foundation that was built over the course of her career. “[I want to] continue to try to help develop the careers of the people who are going to be the next generation [in hematology],” she said.

Had Shipp not been called to the medical and oncology fields early in her life, she had a clear alternative in mind: journalism. In another life, Shipp may have been the one writing this story. Instead, her dedication to research and improving the lives of patients made a lasting mark on the field of hematology and lymphoma.

“At the end of the day, I decided that I wanted to be part of the research rather than write about the research, so I veered to medicine rather than journalism,” Shipp said. 

References

1. Shipp Laboratory. Dana-Farber Cancer Institute. Accessed August 16, 2024. https://shipplab.dana-farber.org/
2. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311-319. doi:10.1056/NEJMoa1411087
3. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283-1294. doi:10.1016/S1470-2045(16)30167-X
4. Nivolumab (Opdivo) for Hodgkin lymphoma. FDA. May 17, 2016. Accessed August 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/nivolumab-opdivo-hodgkin-lymphoma
5. International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1993;329(14):987-994. doi:10.1056/NEJM199309303291402
6. LaCasce AS. The International Prognostic Index: still relevant 30 years later. Haematologica. 2023;108(6):1453-1454. doi:10.3324/haematol.2023.283097
7. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679-690. doi:10.1038/s41591-018-0016-8