Researchers see promising early clinical trials with checkpoint-inhibitor therapies, opening the door for checkpoint-blockade combo therapies.
Immune checkpoint inhibitors are “a new universe” for the treatment of patients with lymphomas, and Hodgkin lymphoma is highly sensitive to PD-1 checkpoint blockade immunotherapy, reported Phillippe Armand, MD, PhD, Sunday, December 6, at the 57th American Society of Hematology (ASH) Annual Meeting in Orlando. He is associate professor of medicine, Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, in Boston.
Dr, ArmandPharmacologic blockade of the programed death-1 protein ligand (PD-1 and PD-L1) has represented “a sea change” in the treatment of solid tumors like melanoma, non-small-cell lung cancer, and renal cell carcinoma, Armand said. PD-1 and PD-L1 blockade can unleash patients’ antitumor immune response.
“In the solid-tumor world, so much is being done with this,” he said.
The unique pathology of Hodgkin lymphoma should “in some sense make it the star of the PD-1 story,” he said. Hodgkin lymphomas almost always involve 9p24.1 amplification, and commonly harbor another gene-amplification mutation at JAK2, both of which result in increased PD-L1 expression.
As a result, a higher proportion of Hodgkin lymphoma cells express PD-L1 protein than any other tumor studied to date, Armand noted.
“Hodgkin lymphoma may have a genetically-driven dependence on the PD-1 pathway for its survival,” he said. Early clinical trial results among patients with Hodgkin Lymphoma show promising early clinical results for nivolumab and pembrolizumab, two checkpoint-inhibitor immunotherapies, Armand said.
Based on expansion-cohort results within phase 1 clinical studies, it appears that “Hodgkin lymphoma is highly sensitive to PD-1 blockade,” he said. Confirmatory phase 2 trials are under way, but Armand believes that they will confirm that these drugs represent a “new and powerful arrow in the quiver” for Hodgkin lymphoma.
Primary mediastinal B cell lymphomas (PMBLs) have genetics similar to Hodgkin, including frequent cancer cell surface expression of PD-L1, making these lymphomas another candidate for immune checkpoint blockade. Early-phase clinical studies of pembrolizumab are under way for patients with PMBL, he said.
Diffuse large B cell lymphomas (DLBCLs) are more heterogeneous and will require a selection strategy to identify which cases might be candidates for checkpoint blockade immunotherapy, Armand said.
PD-1 receptor-level blockade might be a better bet for some lymphomas than PD-L1 blockade, Armand said. That’s because PD-L2 is also deregulated in PMBLs and Hodgkin lymphomas, and PD-L2 genetic translocation mutations have been described; both PD-L1 and PD-L2 can be inhibited with PD-1 blockade immunotherapies, he said.
“We need to better understand the ‘immune architecture’ of tumor cells and their environment,” Armand said. For example, there is a growing understanding that PD-L1 expression in the tumor microenvironment, not just on the surfaces of cancer cells, might affect responses to immunotherapies.
Moreover, “PD-L1 status is not a fixed event,” he cautioned. Cancer cell lines can and do evolve, and expression of PD-L1 can be “dynamic.” Mutational load - how many mutations cancer cells harbor - is important.
“PD-L1-positive tumors are generally good targets but PD-L1-positive tumors are not likely to be the only answer,” he said.
The “checkpoint explosion” has yielded durable response patterns and acceptable safety, but “PD-L1-positive tumors may not be the edge of this universe,” Dr. Armand predicted. “There are many targetable checkpoints.”
That opens the door to immense potential for biologically sensible checkpoint-blockade combination therapies, he said - as well as checkpoint blockade agents combined with chemotherapy, radiation therapy, immunomodulatory drugs, or other classes of immunotherapy agents.
Given all that potential, Armand suggested that immunotherapy may be “too big to fail” and concludes that “it will change the paradigm for Hodgkin lymphoma, and likely for some other lymphomas.”
But it might well be “too big to succeed,” he said: “The optimal combinations might not be owned by the same companies. We need to get samples where they’re needed” for study.