Nivolumab shows promise for Hodgkin's lymphoma
Volume 4, Issue 1, 2015
Early study suggests drug may fight cancer by optimizing immune function.
Stephen M. Ansell, M.D., Ph.D.
A phase I clinical trial of nivolumab found that the immune-boosting drug is a highly effective therapy for Hodgkin's lymphoma.
The multi-institution study, led by the Mayo Clinic Cancer Center, indicated that nivolumab was safe and led to an 87 percent response rate in patients for whom other treatments didn't work. Results of the study were published in the New England Journal of Medicine and presented at the 56th annual meeting of the American Society of Hematology.
The findings support further development of nivolumab, which enhances the immune system's ability to detect and kill cancer cells. Nivolumab has already demonstrated benefit in the treatment of other cancers, including melanoma, renal cell cancer, lung cancer and bladder cancer.
"Nivolumab is a very promising agent that is reasonably well-tolerated and can easily be combined with other agents in the future," said Stephen M. Ansell, M.D., Ph.D., a hematologist and co-lead author of the study. "There is evidence now that you can fight cancer by optimizing your immune function, either by enhancing signals that stimulate the immune response or blocking signals that dampen it."
The immune system's T cells are specifically trained to fight infectious diseases and cancer. When these cells are called to active duty, their extracellular armor is marked with an immune checkpoint protein, a type of off switch called PD1 that can be used to shut down the immune response. Other immune cells carry molecular keys, or ligands, named PD-L1 or PD-L2, which can flip that switch to protect normal tissues from collateral damage.
Cancer cells can co-opt this PD-1 pathway by making their own copy of the keys and using them to turn off T cells before they attack. The malignant cell in Hodgkin's lymphoma, the Reed-Sternberg cell, has very high levels of PD-L1 and PD-L2 on its cell surface.
Therefore, Dr. Ansell and his colleagues hypothesized that using the known immune checkpoint inhibitor nivolumab to block PD1 could prevent these malignant cells from evading immune detection.
Dr. Ansell and his colleagues then analyzed pretreatment tumor specimens from 10 of the patients. They discovered several genetic alterations, such as an increase in the number of PD-L1 and PD-L2 gene copies, that could generate the high levels of ligands detected on the surface of malignant cells.
These findings could explain why Hodgkin's lymphoma patients respond so favorably to a treatment blocking the action of these ligands.
In the phase I study, the researchers gave nivolumab every two weeks to 23 patients with relapsed or refractory Hodgkin's lymphoma who had received previous treatment. Nivolumab appeared to be safe at its highest doses of 3 milligrams per kilogram, with rash and decreased platelet counts being the most common drug-related adverse events.
The researchers observed substantial therapeutic activity, with an objective response rate of 87 percent. Seventeen percent of patients had complete responses, and 70 percent had partial responses. Progression-free survival at 24 weeks was 86 percent.
"There are a number of trials already underway to further validate and confirm these results in Hodgkin's lymphoma," Dr. Ansell said. "I would predict that it won't be long before this particular agent will be approved, and then we will see other studies exploring how to administer it most effectively."