Hodgkin lymphoma (HL) is a cancer that begins in white blood cells called lymphocytes, which play a significant role in the body’s immune system against disease. There have been major advances in the treatment of the disease in the past several years.
A two-in-one drug
One key milestone was the Food and Drug Administration (FDA) approval of brentuximab vedotin, a two-in-one drug consisting of a chemotherapy agent and an antibody, for patients with classical HL who have relapsed, or are at high risk of relapsing, after an autologous stem cell transplant, or who haven’t benefited from at least two multi-drug chemotherapy regimens. Autologous transplants involve the use of a patient’s own cells, rather than donor cells.
An extension of the approval in 2018 allows the drug to be prescribed as an initial treatment, in combination with chemotherapy, for patients with advanced, stage III and IV, classical HL.
The antibody portion of brentuximab vedotin works like a precision-delivery service, carrying the chemotherapy portion directly to the lymphoma cells, where it can have maximum effect. The success of the drug following an autologous transplant led to several clinical trials in which it was tested in patients before a transplant with promising results.
Immune checkpoint inhibitors
Another significant development, stemming directly from research led by Dana-Farber investigators, was the FDA’s 2016 approval of the immunotherapy agent nivolumab and the 2017 approval of pembrolizumab for some patients with recurrent Hodgkin lymphoma. Both drugs are immune checkpoint inhibitors that unleash a potent immune system attack on certain cancer cells.
Dana-Farber’s Margaret Shipp, MD, and her colleagues laid out the rationale for testing nivolumab and pembrolizumab as treatments for HL. They had discovered a chromosomal abnormality that causes two proteins, PD-L1 and PD-L2, to be overproduced on HL cells.
These proteins link up with a complementary protein on immune system T cells to shut down a T-cell assault on cancer. By blocking one such T-cell protein, called PD-1, nivolumab and pembrolizumab thwart that connection, exposing HL to a powerful T-cell attack.
In a phase II clinical trial led by Shipp and Philippe Armand, MD, PhD, nivolumab drove HL into a full or partial remission in 69 percent of patients, all of whom had drug-resistant forms of the disease. These findings led to FDA approval of the drug for patients with classical HL that has come back or progressed after an autologous stem cell transplant.
The success of PD-1 blockade in these patients spurred investigators to launch clinical trials of immune checkpoint inhibitors as an earlier-stage treatment for HL, even as an initial treatment for patients with the disease.
A major focus of current research is identifying which combinations of immune checkpoint inhibitors and other drugs work best in specific patients. Shipp, for example, is analyzing the broad set of genetic mutations that can arise in Hodgkin lymphoma to determine which mutations increase the disease’s vulnerability to certain drug combinations.
“We’re working to develop a biological basis for devising better drug combinations — for understanding which patients are like to benefit the most from specific regimens,” Armand remarks.