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

被引：944

作者：

Advani, Ranjana ^{[1
]}

Flinn, Ian ^{[4
]}

Popplewell, Leslie ^{[2
]}

Forero, Andres ^{[5
]}

Bartlett, Nancy L. ^{[6
]}

Ghosh, Nilanjan ^{[7
]}

Kline, Justin ^{[8
]}

Roschewski, Mark ^{[9
]}

LaCasce, Ann ^{[10
]}

Collins, Graham P. ^{[11
]}

Thu Tran ^{[1
]}

Lynn, Judith ^{[3
]}

Chen, James Y. ^{[3
]}

Volkmer, Jens-Peter ^{[3
]}

Agoram, Balaji ^{[3
]}

Huang, Jie ^{[3
]}

Majeti, Ravindra ^{[1
,3
]}

Weissman, Irving L. ^{[1
,3
]}

Takimoto, Chris H. ^{[3
]}

Chao, Mark P. ^{[3
]}

Smith, Sonali M. ^{[8
]}

机构：

[1] Stanford Univ, Stanford, CA 94305 USA

[2] City Hope Natl Med Ctr, Duarte, CA USA

[3] Forty Seven, Menlo Pk, CA USA

[4] Sarah Cannon Res Inst Tennessee Oncol, Nashville, TN USA

[5] Univ Alabama Birmingham, Birmingham, AL USA

[6] Washington Univ, St Louis, MO 63130 USA

[7] Atrium Hlth, Levine Canc Inst, Charlotte, NC USA

[8] Univ Chicago, Chicago, IL 60637 USA

[9] NCI, Rockville, MD USA

[10] Dana Farber Canc Inst, Boston, MA 02115 USA

[11] Univ Oxford, Oxford, England

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2018年 / 379卷 / 18期

关键词：

B-CELL LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; FOLLICULAR LYMPHOMA; STEM-CELLS; OPEN-LABEL; PHAGOCYTOSIS; OBINUTUZUMAB; MULTICENTER; TARGET; CANCER;

D O I：

10.1056/NEJMoa1807315

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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.)

引用

页码：1711 / 1721

页数：11

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