- PD-1/PD-L1 inhibitors remove normal brakes on the immune system, freeing T cells to attack tumors
- Nivolumab and other compounds are being tested in many cancer types and already show dramatic survival benefits
One of the most exciting new areas in cancer research is a class of monoclonal antibodies that targets immune system checkpoints—specifically, the programmed cell death protein 1 (PD-1) expressed on T-cell membranes. By binding its ligand PD-L1, PD-1 downregulates T cells and prevents autoimmune reactions. Many tumors express the PD-L1 ligand, thereby suppressing the immune response against them. Nivolumab inhibits PD-1, preventing it from binding PD-L1 and enabling T cells to attack tumor cells. “Nivolumab takes the brakes off the immune system, that’s how we explain it to patients,” says Fox Chase medical oncologist Elizabeth Plimack, MD.
Fox Chase is now a study site for multiple clinical trials that include PD-1/PD-L1 inhibitors, which have already yielded impressive results. Cancer types being studied include lung, renal, bladder, and hematologic.
Although Hodgkin’s lymphoma has many effective treatments, they don’t work in all patients, says Fox Chase medical oncologist Michael M. Millenson, MD. PD-1 inhibitors may provide another option. Among a group of 23 patients with relapsed or refractory Hodgkin’s lymphoma who had already been heavily treated, all experienced either stable disease or an objective response to biweekly doses of nivolumab; 17 percent experienced a complete response. By 24 weeks, 86 percent were alive and had not seen their cancer progress. PD-1 inhibitors appear to work particularly well in Hodgkin’s because these lymphomas overexpress the PD-L1 ligand, says Millenson. “The next step will be to explore the use of nivolumab in less heavily pre-treated patients to determine where this may best fit in the overall treatment armamentarium.” The findings are presented by Millenson and his co-authors in the January 22 issue of the New England Journal of Medicine.
Meanwhile, Plimack and her co-authors piloted a Phase I trial of nivolumab in combination with ipilimumab, a monoclonal antibody to CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), another protein that downregulates T-cell activity. Among 44 patients with metastatic renal cell carcinoma (RCC), most of whom had received prior systemic therapy, 43 percent of those receiving nivolumab at a dose rate of 3 mg/kg plus ipilimumab at 1 mg/kg displayed an objective response, as did 48 percent of those on nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg. The majority of patients displayed an ongoing response by the end of the study, and most were progression-free 24 weeks after starting treatment.
In a separate Phase II trial of 168 RCC patients conducted at Fox Chase and other participating sites in the United States, Canada, Finland, and Italy, half of patients survived at least 18 to 25.5 months after treatment with nivolumab, depending on the dosage. Only 11 percent experienced grade 3 or 4 treatment-related adverse events, mostly related to autoimmunity, Plimack and her co-authors reported in the December 1 issue of the Journal of Clinical Oncology.
The drug shows an “acceptable safety profile for most patients,” says Plimack. “We are seeing some patients whose cancer has been controlled or erased in imaging with no chronic side effects.” The researchers are now finalizing the data with the U.S. Food and Drug Administration. “We hope to have FDA approval for the use of nivolumab in renal cell carcinoma early next year.”