The Evolution of Immunotherapy in Lymphoma

In 2016, mature data emerged for novel immunotherapy approaches in both Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Given its impressive activity in relapsed and refractory HL, nivolumab was recently approved by the U.S. Food and Drug Administration (FDA) for use in patients who progressed following autologous stem cell transplantation (ASCT) and brentuximab vedotin. In NHL, cellular therapies, most notably CD19-directed chimeric antigen receptor (CAR) T-cells, demonstrated remarkable activity in refractory diffuse large B-cell lymphoma (DLBCL), leading to numerous ongoing clinical trials with the hope of approval in the near future.

Checkpoint inhibitors directed at program cell death protein 1 (PD-1) and program death-ligand 1 (PDL-1) are associated with meaningful response rates and durable remissions in a subset of patients across a wide array of malignancies from melanoma to lung cancer. With the near-universal upregulation of 9p24, which encodes for PDL-1 and PDL-2 in Reed Sternberg cells, HL has proven to be the model disease for this approach.¹  In patients with relapsed classical HL whose disease recurred following ASCT and had progressed or failed to respond to brentuximab vedotin, treatment with nivolumab produced overall and complete response rates of 66 and 9 percent, respectively.²  Pembrolizumab is associated with remarkably similar activity. In a study of heavily pretreated patients, 71 percent of whom had undergone ASCT, 65 percent of patients responded with 16 percent achieving a complete remission (CR).³  Consistent with other studies of both agents, autoimmune toxicities including hypothyroidism, diarrhea, and pneumonitis were common, but severe adverse events were rare. The activity of PD-1 inhibitors in NHL, however, appears to be less robust, though studies are underway to test the approach in biologically rational lymphoma subtypes such as primary mediastinal large B-cell lymphoma, primary central nervous system lymphoma, and Epstein-Barr virus–associated lymphomas, all of which demonstrate upregulation of PDL-1. Additionally, combination approaches with drugs such as lenalidomide, as well as other immunotherapeutic and novel agents, are ongoing.

Although the outcome of relapsed or refractory HL has improved substantially over the past several years, the prognosis of chemotherapy-refractory DLBCL remains dismal. CAR T-cells have emerged as an important therapeutic strategy. In 2015, Dr. James N. Kochenderfer and colleagues from the National Cancer Institute published results of a trial examining CD19 CAR T-cell with CD28 costimulatory domain.⁴  Patients received lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by T-cell infusion. Of the seven of nine evaluable patients with DLBCL, four achieved a CR and two had a partial remission. Toxicities including cytokine release syndrome (CRS) and neurologic events are common and may be severe. The use of tocilizumab directed at IL-6 has been shown to mitigate CRS, but the etiology and treatment of neurologic complications remain more elusive. More recently, there have been multiple ongoing studies evaluating this approach in DLBCL, as well as mantle cell lymphoma and follicular lymphoma. Data from the multicenter KITE study were presented at the 2016 ASH Annual Meeting as a Late-Breaking Abstract. In the Kite anti-CD19 CAR T-cell study in refractory DLBCL presented as a Late-Breaking Abstract at the 2016 ASH Annual Meeting, 51 evaluable patients received 2 × 10⁶ cells following cyclophosphamide and fludarabine conditioning. The overall response rate was 76 percent, with a 47 percent CR and 29 percent PR. At three months, 39 percent of patients had ongoing responses. Grade 3 cytokine release syndrome and neurologic toxicity occurred in 20 percent and 29 percent of patients, respectively. One patient died of hemophagocytic lymphohistiocytosis.

Looking forward to 2017, combinations of checkpoint inhibitors and CAR T-cells are being studied in trials to assess for further enhancement of T-cell anti-tumor responses. Additionally, T- and NK cell cellular therapies directed at additional tumor associated targets, including Epstein-Barr virus, are underway.