|Combination of anti-CD20 and anti-CD47 antibodies safe and potentially effective in non-Hodgkin’s lymphoma patients|
|Anti-CD20 antibodies have been widely used in regimens for treating B-cell non-Hodgkin’s lymphoma, as CD20 is expressed by B cells and binding with anti-CD20 antibodies triggers antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), natural killer (NK) cell-mediated cytotoxicity, and apoptosis. However, once obtaining resistance to anti-CD20 antibodies, patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma have a poor outcome. CD47, expressed by cancer cells, send a “do-not-eat-me” signal to macrophages in order to avoid immune surveillance, thus anti-CD47 antibodies induce phagocytosis of cancer cells by inhibiting the SIRP (the ligand of CD47)-CD47 axis and T-cell-mediated tumor cell killing, which have been tested pre-clinical trials in many types of cancers including lymphoma. Although the combination of anti-CD20 and anti-CD47 antibodies has been proved to have synergistic antitumor effects in experimental lymphomas, the efficacy of this regimen in patients remains undetermined.
In order to test the efficacy and safety of the combination of anti-CD20 and anti-CD47 antibodies in patients with B-cell lymphoma, the team led by Dr. Ranjana Advani published the results if this phase 1b clinical trial, which has been published in a recent issue of the New England Journal of Medicine (here). A total of 20 patients, who had CD20-expressing DLBCL or follicular lymphoma and were refractory to at least two lines of therapy, were recruited in this phase 1b study. Side-effects during the initial 28 days and the efficacy were assessed. Anti-CD20 antibodies were administered intravenously at a dose of 375 mg/m2, weekly in cycle 1 (starting in week 2), and monthly in cycles 2 to 6. All patients intravenously received anti-CD47 antibodies of 1mg/kg as a priming dose, and one week later were treated with escalating maintenance doses of 10, 20, or 30 mg/kg weekly. Those receiving the dose of 30mg/kg were treated with an additional same dose on day 11. The median duration of treatment was 22 weeks.
Major adverse events in this study were grade 1 and 2, among which chills, headache, anemia, and infusion-related reaction were most common. A case of pulmonary embolism was observed in those receiving the dose of 20mg/kg (1 out of 6), which was relieved by anticoagulation administration without stopping lymphoma treatment. Among those receiving a dose of 30 mg/kg (13 patients), one experienced neutropenia that was relieved by receiving granulocyte colony-stimulating factor without discontinuing tumor treatment, and one suffered idiopathic thrombocytopenic purpura that was relieved by administration of glucocorticoid and immune globulin with discontinuation of tumor therapy.
Assessed by the Lugano Criteria using PET-CT scans, 11 patients had objective response (response rate was 50%), among whom 8 patients experienced complete response and 3 had partial response. Additionally, 3 other patients were categorized as stable disease, making the disease control rate as 64% (14 out of 22).
As the combination of anti-CD20 and anti-CD47 antibodies indicated mild side effects that were less severe than those medicated by program cell death-1 (PD-1) blockage, this combination might have a wider application in clinical practice on the basis of more effective in therapy that will be tested in the future.