CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma

Abstract

Background: The Hu5F9-G4 (hereafter, 5F9) antibody is a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis. 5F9 synergizes with rituximab to eliminate B-cell non-Hodgkin's lymphoma cells by enhancing macrophage-mediated antibody-dependent cellular phagocytosis. This combination was evaluated clinically.

Methods: We conducted a phase 1b study involving patients with relapsed or refractory non-Hodgkin's lymphoma. Patients may have had diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma. 5F9 (at a priming dose of 1 mg per kilogram of body weight, administered intravenously, with weekly maintenance doses of 10 to 30 mg per kilogram) was given with rituximab to determine safety and efficacy and to suggest a phase 2 dose.

Results: A total of 22 patients (15 with DLBCL and 7 with follicular lymphoma) were enrolled. Patients had received a median of 4 (range, 2 to 10) previous therapies, and 95% of the patients had disease that was refractory to rituximab. Adverse events were predominantly of grade 1 or 2. The most common adverse events were anemia and infusion-related reactions. Anemia (an expected on-target effect) was mitigated by the strategy of 5F9 prime and maintenance dosing. Dose-limiting side effects were rare. A selected phase 2 dose of 30 mg of 5F9 per kilogram led to an approximate 100% CD47-receptor occupancy on circulating white and red cells. A total of 50% of the patients had an objective (i.e., complete or partial) response, with 36% having a complete response. The rates of objective response and complete response were 40% and 33%, respectively, among patients with DLBCL and 71% and 43%, respectively, among those with follicular lymphoma. At a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma, 91% of the responses were ongoing.

Conclusions: 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. (Funded by Forty Seven and the Leukemia and Lymphoma Society; ClinicalTrials.gov number, NCT02953509 .).

Figure 1.. Adverse Events Due to Hu5F9-G4 (5F9), Rituximab, or Both and On-Target Anemia Effect of 5F9.

Panel A shows the adverse events that occurred in at least 10% of the patients during treatment. Panel B shows the levels of hemoglobin and reticulocytes over time in a representative patient (with diffuse large B-cell lymphoma) during the study. The priming dose of 1 mg of 5F9 per kilogram of body weight was received on day 1 (green arrow). The patient received maintenance doses of 30 mg of 5F9 per kilogram (blue arrows).

Figure 2.. Pharmacodynamic Data on CD47-Receptor Occupancy, Tumor Penetrance, and Responses in Two Patients.

Panel A shows CD47-receptor occupancy on peripheral white cells and red cells. The dashed vertical line at day 29 shows the transition from receipt of the dose weekly to receipt every 2 weeks. Panel B shows 5F9 antibody tumor penetrance in a tumor supraclavicular lymph node in a patient with DLBCL who was treated with 20 mg of 5F9 per kilogram. 5F9 penetrance was measured by immunohistochemical testing with detection by anti-IgG4 staining. Panel C shows positron-emission tomographic–computed tomographic (CT) scans of a 58-year-old woman (Patient 18) with heavily pretreated DLBCL (four previous lines of therapy) who had had rapid disease progression 3 months after undergoing autologous transplantation. The patient had daily fevers before enrollment, which resolved within a few weeks after the initiation of study therapy. The patient had a complete response at 8 weeks, including resolution of bone marrow disease as assessed by means of bone marrow aspirate and biopsy. Panel D shows CT scans of a 56-year-old man (Patient 16) who had primary refractory DLBCL (two previous lines of therapy) with bulky disease. The patient had a complete remission during treatment. Arrows indicate hypermetabolic pleural thickening from previous surgery and not lymphoma.

Figure 3.. Change in Tumor-Lesion Size and Duration of Responses with 5F9 and Rituximab.

Panel A shows a waterfall plot of the best overall change in the size of tumor target lesions among patients with diffuse large B-cell lymphoma (DLBCL; indicated by an asterisk) or follicular lymphoma, according to the maintenance dose received. Plots of the percentage changes in the tumor burden of target lesions are shown graphically. All the tumor lesions were measured in centimeters. A target lesion size of “too small to measure” was imputed as 0.5 cm², and “not visible” as 0 cm². One patient could not be evaluated because of discontinuation of the study before the first protocol-specified response assessment. Thresholds regarding progressive disease and partial response according to the Lugano criteria are indicated by dashed lines. Per the Lugano criteria, patients met the criteria for response by either a decrease in the tumor lesion size as assessed by computed tomography (data shown) or a decrease in metabolic activity as assessed by positron-emission tomography (data not shown). Panel B shows spider plots of data from patients with DLBCL, according to response to treatment, and Panel C shows data from patients with follicular lymphoma; the median duration of response and median follow-up are also shown. A plus sign indicates that the response was ongoing at the time of data cutoff. The dashed line at 0 indicates no change from baseline.