Hu5F9-G4 联合利妥昔单抗阻断 CD47 在非霍奇金淋巴瘤中的作用。
CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma.
机构信息
From Stanford University, Stanford (R.A., T.T., R.M., I.L.W.), City of Hope, Duarte (L.P.), and Forty Seven, Menlo Park (J.L., J.Y.C., J.-P.V., B.A., J.H., R.M., I.L.W., C.H.T., M.P.C.) - all in California; Sarah Cannon Research Institute-Tennessee Oncology, Nashville (I.F.); University of Alabama at Birmingham, Birmingham (A.F.); Washington University in St. Louis, St. Louis (N.L.B.); Levine Cancer Institute-Atrium Health, Charlotte, NC (N.G.); University of Chicago, Chicago (J.K., S.M.S.); National Cancer Institute, Rockville, MD (M.R.); Dana-Farber Cancer Institute, Boston (A.L.); and University of Oxford, Oxford, United Kingdom (G.P.C.).
出版信息
N Engl J Med. 2018 Nov 1;379(18):1711-1721. doi: 10.1056/NEJMoa1807315.
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 .).
背景
Hu5F9-G4（简称 5F9）抗体是一种巨噬细胞免疫检查点抑制剂，可阻断诱导肿瘤细胞吞噬作用的 CD47。5F9 与利妥昔单抗联合使用，通过增强巨噬细胞介导的抗体依赖性细胞吞噬作用，消除 B 细胞非霍奇金淋巴瘤细胞。该联合疗法已进行临床评估。
方法
我们进行了一项 1b 期研究，纳入了复发或难治性非霍奇金淋巴瘤患者。患者可能患有弥漫性大 B 细胞淋巴瘤（DLBCL）或滤泡性淋巴瘤。5F9（起始剂量为 1 毫克/千克，静脉注射，每周维持剂量为 10 至 30 毫克/千克）与利妥昔单抗联合使用，以确定安全性和疗效，并确定 2 期剂量。
结果
共有 22 名患者（15 名患有 DLBCL，7 名患有滤泡性淋巴瘤）入组。患者接受中位数为 4 次（范围 2 至 10 次）的既往治疗，95%的患者对利妥昔单抗耐药。不良事件主要为 1 级或 2 级。最常见的不良事件是贫血和输注相关反应。贫血（预期的靶标效应）通过 5F9 起始和维持剂量方案得到缓解。剂量限制副作用罕见。选择 30 毫克/千克的 5F9 作为 2 期剂量，可导致循环白细胞和红细胞上约 100%的 CD47 受体占有率。50%的患者有客观（即完全或部分）反应，其中 36%有完全反应。DLBCL 患者的客观反应率和完全反应率分别为 40%和 33%，滤泡性淋巴瘤患者分别为 71%和 43%。在 DLBCL 患者的中位随访 6.2 个月和滤泡性淋巴瘤患者的中位随访 8.1 个月时，91%的反应仍在持续。
结论
巨噬细胞检查点抑制剂 5F9 与利妥昔单抗联合使用在侵袭性和惰性淋巴瘤患者中显示出有前景的疗效。在这项初步研究中未观察到临床显著的安全事件。（由 Forty Seven 和白血病和淋巴瘤协会资助；ClinicalTrials.gov 编号，NCT02953509）。
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