This year’s Ernest Beutler Lecture and Prize, which recognizes two outstanding researchers in basic science and translational/clinical research for a single topic, was awarded to Dr. Margaret A. Shipp from Dana Farber/Harvard Cancer Center and Dr. Stephen M. Ansell from the Mayo Clinic. Their seminal work in elucidating the importance of PD-1/PD-L1 pathway in classical Hodgkin lymphoma (cHL) has revolutionized the treatment of this disease. Drs. Shipp and Ansell delivered inspirational lectures on Monday, December 13.
In general, response rates in solid tumors to checkpoint inhibitors are approximately 20 to 30 percent. Checkpoint blockade has been evaluated in many hematologic malignancies, with mixed results. However, two notable exceptions are cHL and primary mediastinal B-cell lymphoma (PMBCL). Response rate to single agent PD-1 blockade in cHL is 70 to 90 percent!
The success of checkpoint blockade in cHL and PMBCL is due to their unique biology — the focus of Dr. Shipp’s research. As she explained, “One of the things that is really interesting and unusual about HL [is that] only about 1 to 2 percent of the cells are the malignant cells. The rest of the lymphoma is made up of an inflammatory immune cell infiltrate that doesn't work very well.” Copy number alterations of 9p24.1, which is the locus of the PD-L1 gene, is present in virtually all Reed-Sternberg cells and the majority of neoplastic cells in PMBCL. PD-L1 is present on normal macrophages and dendritic cells and acts as a “break” to the immune system, contributing to formation of peripheral tolerance. When PD-L1 is expressed on the surface of cancer cells, it allows cancer cells to evade immune detection and destruction. Copy number alterations of 9p24.1, such as amplification, lead to higher expression of PD-L1 on the malignant cells resulting in immune evasion.
The above findings resulted in various trials evaluating the efficacy of nivolumab and pembrolizumab in cHL and PMBCL. “It was surprisingly effective in phase I studies,” explained Dr. Ansell. Remarkably, PD-1 blockade as a single agent demonstrated a 70 percent overall response rate in heavily pretreated patients with cHL. The impressive efficacy was also seen in PMBCL. Furthermore, Dr. Shipp and Dr. Ansell demonstrated that the degree of PD-L1 expression is associated with responses in cHL. Nivolumab and pembrolizumab has since been approved by the U.S. Food and Drug Administration for treatment of relapsed and/or refractory (R/R) cHL and PMBCL. The combination of nivolumab + AVD (doxorubicin, vinblastine, and dacarbazine) is being evaluated in the frontline setting for cHL versus brentuximab vedotin + AVD, in the SWOG S1826. “This highlights the progress that has been made in the field,” said Dr. Ansell.
Unfortunately, checkpoint blockade has not been effective in other B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma. PD-L1 expression is “not genetically driven in common or garden-variety large-cell lymphoma,” said Dr. Ansell. He explained further, “It seems that you need genetically driven expression in DLBCL and follicular lymphoma.” Selected groups of aggressive B-cell lymphomas, such as central nervous system, testicular, and Epstein-Barr virus–positive lymphomas appear to have overexpression of PD-L1 through the activation of JAK-STAT pathway and may benefit from checkpoint blockade. These studies are ongoing.
In contrary to DLBCL, there are hints of anti-PD-L1 activity seen in T-cell lymphoma with studies showing response rate of 30 to 35 percent. However, there have been subsets of T-cell lymphomas such as adult T-cell leukemia/lymphoma that had hyperprogression — accelerated progression of disease — after checkpoint therapy. “It is as if we are poking the bear,” said Dr. Ansell, “We must progress with caution.”
The future direction of checkpoint inhibition is broad. “The biggest challenge currently is to determine when in a patient's disease course to use these approaches and how to combine them with other standard therapies,” explained Dr. Ansell. Combination therapies with checkpoint inhibitors targeting other pathways (such as anti-LAG3, anti-TIM3, and anti-TIGIT) are in the pipeline, and its synergy with chimeric antigen receptor T-cell therapy is also under investigation.
Interested readers should tune in to the Education Program session “Hodgkin Lymphoma: Cure and Optimal Survivorship” led by Dr. Kristie A. Blum, Scientific Program session “Immune Evasion and Immunotherapy in Myeloid Malignancies” led by Dr. Satu Mustjoki, and oral abstract session 624 “Hodgkin Lymphomas and T/NK cell Lymphomas: Hodgkin Lymphoma Clinical Trials” moderated by Dr. Rod Ramchandren and Dr. Matthew Mei.
Will the “pembros and nivos” be daily therapy in the hematology world? Thanks to the work of Dr. Shipp, Dr. Ansell, and many other researchers, the exciting time is hopefully coming soon.
Drs. Jeong and Goodman indicated no relevant conflicts of interest.
