Reprogramming the immune system
Nivolumab, another monoclonal antibody that blocks the PD-1 pathway, is being investigated in a number of lymphoid malignancies, including HL, DLBCL, and T-cell lymphomas.
In a phase 1 study of nivolumab in 81 patients with relapsed or refractory lymphoid malignancies, the best preliminary overall response has been in FL and DLBCL patients, with an objective response rate of 40% and 36%, respectively, including 1 PR and 3 PRs in each subtype.
“I think what is important,” Dr Ansell said, “is that the side effects, as expected, were mainly immune-mediated, not as dramatic as have been seen with other agents, and very similar to what has been seen in solid tumor studies.”
Dr Ansell pointed out that the response rates with nivolumab varied widely by histology, suggesting that “we have a lot to learn about why patients benefit and who exactly benefits.”
There were no responses in patients with multiple myeloma or primary mediastinal B-cell lymphoma, although many patients achieved stable disease.
“Hodgkin lymphoma was completely different,” Dr Ansell said, “and there were responses in virtually every patient.”
Of 23 patients treated with nivolumab, 20 responded—4 achieved a CR and 16 a PR—including patients who had failed autologous HSCT and brentuximab vedotin treatment. Eleven patients, including 2 with CRs, have an ongoing response, some approaching 2 years. So the responses have been durable, Dr Ansell noted.
Yet another PD-1 antibody, pembrolizumab, has prompted reduction in tumor burden in HL in all but 2 of 29 evaluable patients, including 6 CRs and 13 PRs. The median duration of response has not yet been reached, and the side effect profile was similar to what has been seen with nivolumab and in solid tumors.
Activating immune stimulatory signals
Another approach to boosting the immune system is to activate immune stimulatory signals, eg, CD27 and CD40, and get a benefit that way. Varlilumab (CDX-1127) is an unconjugated monoclonal antibody that binds CD27 and activates CD27-expressing T cells.
In a phase 1 trial of varlilumab in 24 lymphoma patients, investigators found no significant depletion in absolute lymphocyte counts, T cells, or B cells. “Not quite the same success story,” Dr Ansell said, with a response—a CR—in only 1 patient.
Investigators did observe, however, evidence of increased soluble CD27, a reduction of circulating Tregs, and the induction of pro-inflammatory cytokines.
And in a phase 1 study of the anti-CD40 monoclonal antibody dacetuzumab in recurrent NHL, “the response rate was disappointingly low,” Dr Ansell said.
Investigators observed 6 objective responses, including 1 CR and 5 PRs, and a decrease in tumor size in approximately one-third of the 50 patients treated.
The investigators of the subsequent phase 2 trial did not want to take the agent forward for further study, Dr Ansell noted, “but there are antibodies now being developed in this space that will hopefully be more effective and create a greater benefit.”
Optimizing immune function
Dr Ansell suggested there are 3 main approaches to treating patients. One is going directly after the malignant cells and depleting them. A second is to inhibit critical pathways that the malignant cell is dependent upon, “starving them, if you like.” The third way is to activate the immune system and thereby create a greater benefit for patients.
“[P]robably our best strategy is to use all 3 in a reprogram approach,” he said. “Because unless you target each one of these areas, the likelihood is that the other sides of the 3-legged stool will take over.”
“This is an encouraging and exciting time for immune checkpoints therapy and an encouraging and exciting time for immune therapies in general. I think this is really the new frontier in lymphomas.” 
