Combination of Macrophage Immune Checkpoint Inhibitor and Rituximab in Non-Hodgkin Lymphoma
In a phase Ib study reported in The New England Journal of Medicine, Advani et al found that the combination of rituximab (Rituxan) and the CD47-blocking monoclonal antibody Hu5F9-G4 (or 5F9), a macrophage immune checkpoint inhibitor, was active in patients with non-Hodgkin lymphoma. CD47, which is overexpressed in many cancers, acts as an antiphagocytic signal that permits immune evasion of macrophages and other phagocytes.
The study included 22 patients, 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma. Patients had received a median of 4 previous therapies and 95% had disease that was refractory to rituximab. 5F9 was given intravenously at a priming dose of 1 mg/kg and at weekly maintenance doses of 10 to 30 mg/kg, with treatment continuing until disease progression, lack of clinical benefit, or unacceptable toxicity. Rituximab was given at 375 mg/m2 weekly in cycle 1 starting in week 2 and then monthly in cycles 2 through 6.
Toxicity
The most common treatment-related adverse events of any grade were chills (41%), headache (41%), anemia (41%), and infusion-related reactions (36%). Anemia was an expected on-target effect that was to be mitigated via the strategy of 5F9 prime and maintenance dosing. Three dose-limiting effects were observed, consisting of grade 3 pulmonary embolism in a patient found to have an occult deep-vein thrombosis, grade 4 neutropenia, and grade 3 idiopathic thrombocytopenia purpura.
The 5F9 dose selected for phase II study was 30 mg/kg. Pharmacodynamic analysis indicated approximately 100% CD47-receptor occupancy on circulating white and red cells at this dose.
Responses
The median duration of treatment was 22 weeks. Objective response was observed in 11 patients (50%), with complete response in 8 (36%). Response was observed in 6 of 15 patients with DLBCL, with complete response in 5, and in 5 of 7 with follicular lymphoma, with complete response in 3. A total of 91% of responses were ongoing at a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma.
The investigators concluded, “The macrophage checkpoint inhibitor 5F9 combined with rituximab showed promising activity in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study.”
The study was funded by Forty Seven and the Leukemia and Lymphoma Society.
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