Medical advances tend to unfold slowly over many years, fueled by successive clinical studies that build upon each other and together provide the evidence needed to change patient care. A key illustration of this point comes from a recent phase 3 clinical trial, published last October in the New England Journal of Medicine (NEJM), which showed that combining nivolumab, an immune checkpoint inhibitor, with a standard chemotherapy regimen significantly improved outcomes for patients with newly diagnosed, advanced-stage Hodgkin lymphoma compared to conventional treatment.
“This treatment appears to be more effective and less toxic — and really sets a new standard for treating patients with newly diagnosed Hodgkin lymphoma,” said Margaret Shipp, MD, Chief of the Division of Hematologic Neoplasia at Dana-Farber and a co-author of the NEJM study.
These practice-changing findings have been years in the making, propelled by early work in Shipp’s laboratory that helped unlock the biology of these tumors.
“One of the major areas of interest in our lab is to understand the comprehensive genetic signatures of specific lymphoid malignancies, because that understanding gives insights into tumor biology, which in turn helps us think more rationally about treatment,” she said.
Hodgkin lymphoma is a cancer that typically affects young adults, from teens to those in their early thirties, but can also emerge in older children. It is also somewhat unusual among tumor types in that it carries a genetic alteration that suggests a unique reliance on signaling through the PD1 protein. Drugs that block these signals are among a key class of drugs, known as immune checkpoint inhibitors, which have transformed the treatment of a variety of cancer subtypes.
Several years ago, Shipp and her colleagues initiated a series of studies to examine the genetic signatures of tumor cells from Hodgkin lymphoma patients. This work was particularly challenging because only a small fraction of the cells within the tumors — about 2% — are malignant. The rest are immune cells from the body that are trying to mount a response to the abnormal growth. So, they needed sophisticated methods to isolate these tumors cells and analyze their genetic material.
Their efforts paid off. Shipp’s team uncovered a striking genetic abnormality — a piece of chromosome 9 (known as 9p24) that was amplified, meaning the tumor cells harbor many more copies of this stretch of DNA than the typical two copies.
“So then, the next question was, what’s on chromosome 9p24?” recalled Shipp. The answer: the gene that encodes the ligand for the PD1 protein.
This discovery, which was reported in 2010 in the journal Blood, suggested a potential vulnerability in Hodgkin lymphoma cells that could be exploited by a drug that blocks PD1 activity. At the time, these therapies had just entered the clinic and were primarily being used to treat melanoma. The early data produced by Shipp’s team provided a motivation for launching the first clinical tests of nivolumab as a treatment for Hodgkin lymphoma.
A phase 1 clinical trial examined the therapy in patients with relapsed or refractory disease, meaning their tumors did not respond to available treatments. The initial results, which were published in NEJM in 2015, showed that 20 out of 23 patients responded to the treatment. Those findings quickly led to an U.S. Food and Drug Administration (FDA) approval for this indication about a year later.
“In less than ten years, we’ve gone from the publication of the initial results of the efficacy of PD1 blockade when used as a single agent in patients with relapsed-refractory Hodgkin’s lymphoma to now evidence of improved efficacy in the frontline setting,” said Shipp. “And that’s important because PD1 blockade is now included as part of every aspect of treatment for this cancer.”
Beyond the impact this work has had on patients, it underscores the significance of laboratory research.
“This is a prime example of where research has helped inform new treatment directions, and that’s something Dana-Farber does uniquely well,” said Shipp. “Here, there’s a sustained commitment to understanding the biology and genetics of specific diseases and then taking that information and applying it to patients.”